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WO2003006064A1 - Pharmaceutical formulation for the intramuscular administration of fulvestrant - Google Patents

Pharmaceutical formulation for the intramuscular administration of fulvestrant Download PDF

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Publication number
WO2003006064A1
WO2003006064A1 PCT/GB2002/003092 GB0203092W WO03006064A1 WO 2003006064 A1 WO2003006064 A1 WO 2003006064A1 GB 0203092 W GB0203092 W GB 0203092W WO 03006064 A1 WO03006064 A1 WO 03006064A1
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WO
WIPO (PCT)
Prior art keywords
per volume
formulation
weight
fulvestrant
weight per
Prior art date
Application number
PCT/GB2002/003092
Other languages
French (fr)
Inventor
Julie Kay Cahill
Paul Richard Gellert
Alan Marshall Irving
Original Assignee
Astrazeneca Ab
Astrazeneca Uk Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from GBGB0116619.8A external-priority patent/GB0116619D0/en
Application filed by Astrazeneca Ab, Astrazeneca Uk Limited filed Critical Astrazeneca Ab
Priority to JP2003511869A priority Critical patent/JP2004534093A/en
Priority to CA002453111A priority patent/CA2453111A1/en
Priority to HU0400115A priority patent/HUP0400115A3/en
Priority to EP02740940A priority patent/EP1406662A1/en
Priority to KR10-2004-7000153A priority patent/KR20040010841A/en
Priority to IL15957602A priority patent/IL159576A0/en
Priority to BR0210898-4A priority patent/BR0210898A/en
Publication of WO2003006064A1 publication Critical patent/WO2003006064A1/en
Priority to IS7097A priority patent/IS7097A/en
Priority to NO20040047A priority patent/NO20040047L/en

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the invention relates to a sustained release pharmaceutical formulation adapted for administration by injection containing the compound fulvestrant, 7 ⁇ -[9-(4,4, 5,5,5- 5 pentafluoropentylsulphinyl)nonyl]oestra-l,3,5(10)-triene-3,17 ⁇ -diol, at concentration of at least lOOmg/ml in solution in a ricinoleate vehicle which additionally comprises at least one alcohol and a non-aqueous ester solvent which is miscible in the ricinoleate vehicle.
  • Oestrogen deprivation is fundamental to the treatment of many benign and malignant diseases of the breast and reproductive tract. In premenopausal women, this is achieved by 0 the ablation of ovarian function through surgical, radiotherapeutic, or medical means, and, in postmenopausal women, by the use of aromatase inhibitors.
  • oestrogen withdrawal is to antagonise oestrogens with antioestrogens.
  • drugs that bind to and compete for oestrogen receptors (ER) present in the nuclei of oestrogen-responsive tissue.
  • ER oestrogen receptors
  • Conventional nonsteroidal antioestrogens, such 5 as tamoxifen, compete efficiently for ER binding but their effectiveness is often limited by the partial agonism they display, which results in an incomplete blockade of oestrogen-mediated activity (Furr and Jordan, Pharmacology & Therapeutics, 25: 127-206, 1984; May and
  • Estrogen Receptor-Downregulators E.R.D.
  • Steroidal analogues of oestradiol with an alkylsulphinyl side chain in the 7 ⁇ position, provided the first examples of compounds devoid of oestrogenic activity (Bowler et al 1989).
  • fulvestrant 7 ⁇ -[9-(4,4,5,5,5-Pentafluoropentylsul ⁇ hinyl)nonyl]oestra-l,3-5(10)-triene-3,17 ⁇ -diol, or ICI 182,780, has been allocated the international non-proprietary name fulvestrant, which is used hereinafter.
  • fulvestrant we include pharmaceutically-acceptable salts thereof and any possible solvates of either thereof.
  • Fulvestrant binds to ER with an affinity similar to that of oestradiol and completely blocks the growth stimulatory action of oestradiol on human breast cancer cells in vitro; it is more potent and more effective than tamoxifen in this respect. Fulvestrant blocks completely the uterotrophic action of oestradiol in rats, mice and monkeys, and also blocks the uterotrophic activity of tamoxifen.
  • fulvestrant Because fulvestrant has none of the oestrogen-like stimulatory activity that is characteristic of clinically available antioestrogens such as tamoxifen or toremifene, it may offer improved therapeutic activity characterised by more rapid, complete, or longer-lasting tumour regression; a lower incidence or rate of development of resistance to treatment; and a reduction of tumour invasiveness.
  • fulvestrant In intact adult rats, fulvestrant achieves maximum regression of the uterus at a dose which does not adversely affect bone density or lead to increased gonadotrophin secretion. If also true in humans, these findings could be of extreme importance clinically. Reduced bone density limits the duration of oestrogen-ablative treatment for endometriosis. Fulvestrant does not block hypothalamic ER. Oestrogen ablation also causes or exacerbates hot flushes and other menopausal symptoms; fulvestrant will not cause such effects because it does not cross the blood-brain barrier. European Patent Application No. 0 138 504 discloses that certain steroid derivatives are effective antioestrogenic agents. The disclosure includes information relating to the preparation of the steroid derivatives.
  • Example 35 there is the disclosure within Example 35 of the compound 7 ⁇ -[9-(4,4,5,5,5-pentafluoropentylsulphinyl)nonyl]oestra- 1,3,5(10)-triene-3 , 17 ⁇ -diol, which compound is specifically named in Claim 4. It is also disclosed that the compounds of that invention may be provided for use in the form of a pharmaceutical composition comprising a steroid derivative of the invention together with a pharmaceutically-acceptable diluent or carrier. It is stated therein that the composition can be in a form suitable for oral or parenteral administration.
  • Fulvestrant shows, along with other steroidal based compounds, certain physical properties which make formulation of these compounds difficult. Fulvestrant is a particularly lipophilic molecule, even when compared with other steroidal compounds, and its aqueous solubility is extremely low at around 10 ngml' 1 (this is an estimate from a water/solvent mixture solute since measurements this low could not be achieved in a water only solute).
  • sustained release injectable steroidal formulations which have been commercialised. Commonly these formulations use oil as a solvent and wherein additional excipients may be present.
  • Example 3 an oil based injection formulation of fulvestrant is described which comprises 50mg of fulvestrant, 400mg of benzyl alcohol and sufficient castor oil to bring the solution to a volume of 1 ml.
  • Manufacture at a commercial scale of a formulation as described in US 5,183,814 will be complicated by the high alcohol concentration. Therefore, there is a need to lower the alcohol concentration in fulvestrant formulations whilst preventing precipitation of fulvestrant from the formulation.
  • fulvestrant is significantly more soluble in castor oil than any of the other oils tested.
  • the greater solvating ability of castor oil for steroidal compounds is known and is attributed to the high number of hydroxy groups of ricinoleic acid, which is the major constituent of the fatty acids within the triglycerides present in castor oil - see (Riffkin et.al. J. Pharm. Sci., (1964), 53, 891).
  • a pharmaceutical formulation adapted for intramuscular injection comprising 100 mg/ml or more of fulvestrant, 10 % or more weight of a pharmaceutically acceptable alcohol per volume of formulation vehicle, 5 % or more weight of a pharmaceutically acceptable non-aqueous ester solvent per volume of formulation vehicle and 5 % or more weight of ricinoleate excipient per volume of formulation vehicle provided the formulation vehicle comprises at least 5 % weight of ethanol per volume of formulation vehicle and provided that the following formulation is excluded: fulvestrant up to 102 mg/ml, 15 % weight of ethanol per volume of formulation vehicle, 15 % weight of benzyl alcohol per volume of formulation vehicle, 15 % weight of benzyl benzoate per volume of formulation vehicle and 30 % or more weight of ricinoleate excipient per volume of formulation vehicle.
  • a preferred pharmaceutical formulation adapted for intramuscular injection is one comprising 105 mg/ml or more of fulvestrant, 10 % or more weight of a pharmaceutically acceptable alcohol per volume of formulation vehicle, 5 % or more weight of a pharmaceutically acceptable non-aqueous ester solvent per volume of formulation vehicle and 5 % or more weight of ricinoleate excipient per volume of formulation vehicle provided the formulation comprises at least 5 % weight of ethanol per volume of formulation vehicle.
  • a more preferred pharmaceutical formulation adapted for intramuscular injection is one comprising 110 mg/ml or more of fulvestrant, 10 % or more weight of a pharmaceutically acceptable alcohol per volume of formulation vehicle, 5 % or more weight of a pharmaceutically acceptable non-aqueous ester solvent per volume of formulation vehicle and 5 % or more weight of ricinoleate excipient per volume of formulation vehicle provided the formulation vehicle comprises at least 5 % weight of ethanol per volume of formulation vehicle.
  • a more preferred pharmaceutical formulation adapted for intramuscular injection is one comprising 1 15 mg/ml or more of fulvestrant, 10 % or more weight of a pharmaceutically acceptable alcohol per volume of formulation vehicle, 5 % or more weight of a pharmaceutically acceptable non-aqueous ester solvent per volume of formulation vehicle and 5 % or more weight of ricinoleate excipient per volume of formulation vehicle provided the formulation vehicle comprises at least 5 % weight of ethanol per volume of formulation vehicle.
  • a more preferred pharmaceutical formulation adapted for intramuscular injection is one comprising 120 mg/ml or more of fulvestrant, 10 % or more weight of a pharmaceutically acceptable alcohol per volume of formulation vehicle, 5 % or more weight of a pharmaceutically acceptable non-aqueous ester solvent per volume of formulation vehicle and 5 % or more weight of ricinoleate excipient per volume of formulation vehicle provided the formulation vehicle comprises at least 5 % weight of ethanol per volume of formulation vehicle.
  • a more preferred pharmaceutical formulation adapted for intramuscular injection is one comprising 130 mg/ml or more of fulvestrant, 15 % or more weight of a pharmaceutically acceptable alcohol per volume of formulation vehicle, 5 % or more weight of a pharmaceutically acceptable non-aqueous ester solvent per volume of formulation vehicle and 5 % or more weight of ricinoleate excipient per volume of formulation vehicle provided the formulation vehicle comprises at least 5 % weight of ethanol per volume of formulation vehicle.
  • a more preferred pharmaceutical formulation adapted for intramuscular injection is one comprising 140 mg/ml or more of fulvestrant, 15 % or more weight of a pharmaceutically acceptable alcohol per volume of formulation vehicle, 12.5 % or more weight of a pharmaceutically acceptable non-aqueous ester solvent per volume of formulation vehicle and 5 % or more weight of ricinoleate excipient per volume of formulation vehicle provided the formulation vehicle comprises at least 10 % weight of ethanol per volume of formulation vehicle.
  • a more preferred pharmaceutical formulation adapted for intramuscular injection is one comprising 150 mg/ml or more of fulvestrant, 15 % or more weight of a pharmaceutically acceptable alcohol per volume of formulation vehicle, 17.5 % or more weight of a pharmaceutically acceptable non-aqueous ester solvent per volume of formulation vehicle and
  • a pharmaceutical formulation adapted for intramuscular injection is one comprising 150 mg/ml or more of fulvestrant, 15 % or more weight of a pharmaceutically acceptable alcohol per volume of formulation vehicle, 17.5 % or more weight of a pharmaceutically acceptable non-aqueous ester solvent per volume of formulation vehicle and 5 % or more weight of ricinoleate excipient per volume of formulation vehicle.
  • a pharmaceutical formulation having a solubility for fulvestrant of at least Y mg/ml adapted for intramuscular injection comprising;
  • ETOH benzyl alcohol
  • BA benzyl benzoate
  • a preferred pharmaceutical formulation is one wherein Y is selected from the group consisting of 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 170, 180, 190, and
  • a more preferred pharmaceutical formulation is one wherein Y is selected from the group consisting of 120, 125, 130, 135, 140, 145, 150, 155, 160, 170, 180, 190, and 200.
  • a more preferred pharmaceutical formulation is one wherein Y is selected from the group consisting of 150, 155, 160, 170, 180, 190 and 200.
  • a more preferred pharmaceutical formulation is one wherein Y is selected from 150, 155, 160, 170, 180, 190 and 200 and the formulation comprises at least 150mg/ml of fulvestrant.
  • a more preferred pharmaceutical formulation is one wherein Y is 200 and the formulation comprises at least 200mg/ml of fulvestrant.
  • a pharmaceutical formulation comprising fulvestrant at a concentration of at least 100 mg/ml in which the formulation is adapted for intra-muscular injection into a human and which is capable after injection of attaining a therapeutically significant blood plasma fulvestrant concentration in a human for at least 2 months and provided that the following formulation is excluded: fulvestrant up to 102 mg/ml, 15 % weight of ethanol per volume of formulation vehicle, 15 % weight of benzyl alcohol per volume of formulation vehicle, 15 % weight of benzyl benzoate per volume of formulation vehicle and 30 % or more weight of ricinoleate excipient per volume of formulation vehicle.
  • a pharmaceutical formulation comprising fulvestrant in which the formulation is adapted for intra-muscular injection into a human and which is capable after injection of attaining a therapeutically significant blood plasma fulvestrant concentration in a human for at least 2 months.
  • a pharmaceutical formulation comprising fulvestrant at a concentration of at least 100 mg/ml in which the formulation is adapted for intra-muscular injection into a human and which is capable after injection of attaining a therapeutically significant blood plasma fulvestrant concentration in a human for at least 2 months.
  • a pharmaceutical formulation comprising fulvestrant at a concentration of at least 150 mg/ml in which the 5 formulation is adapted for intra-muscular injection into a human and which is capable after injection of attaining a therapeutically significant blood plasma fulvestrant concentration in a human for at least 2 months.
  • a pharmaceutical formulation comprising fulvestrant at a concentration of at least 200 mg/ml in which the 10 formulation is adapted for intra-muscular injection into a human and which is capable after injection of attaining a therapeutically significant blood plasma fulvestrant concentration in a human for at least 2 months.
  • a pharmaceutical formulation comprising fulvestrant at a concentration of at least 300 mg/ml in which the 15 formulation is adapted for intra-muscular injection into a human and which is capable after injection of attaining a therapeutically significant blood plasma fulvestrant concentration in a human for at least 2 months.
  • any one of the following pharmaceutical formulations comprising about: 20 i)
  • the term "comprising about” in this context means that the numerical value assigned to each component of the formulation may be varied independently to accommodate manufacturing specifications encountered by a skilled person when making up the formulations. Typically this means plus or minus 5%, more preferably plus or minus 4%>, more preferably plus or minus 3%>, more preferably plus or minus 2%, more preferably plus or minus 1%. In a preferred embodiment, more variation in drug level is allowed compared with other components. For example:
  • the individual formulations described herein may comprise further excipients commonly used in the formulation field including, for example, an antioxidant preservative, a colorant or a surfactant.
  • any one of the following pharmaceutical formulations i)
  • a preferred pharmaceutical formulation described herein is one wherein the pharmaceutically-acceptable alcohol is a mixture of ethanol and benzyl alcohol.
  • a preferred pharmaceutical formulation described herein is one wherein the pharmaceutically-acceptable non-aqueous ester solvent is selected from benzyl benzoate, ethyl oleate, isopropyl myristate, isopropyl palmitate or a mixture of any thereof. 30
  • a preferred pharmaceutical formulation described herein is one wherein the pharmaceutically-acceptable non-aqueous ester solvent is benzyl benzoate.
  • a preferred pharmaceutical formulation described herein is one wherein the ricinoleate excipient is castor oil.
  • a pharmaceutical formulation adapted for intramuscular injection comprising 100 mg/ml or more of fulvestrant, 10 % > or more weight of a pharmaceutically acceptable alcohol per volume of pharmaceutical formulation, 5 % or more weight of a pharmaceutically acceptable non-aqueous ester solvent 5 per volume of pharmaceutical formulation and 5 %> or more weight of ricinoleate excipient per volume of pharmaceutical formulation provided: a) the pharmaceutical formulation comprises at least 5 % weight of ethanol per volume of pharmaceutical formulation; b) if the pharmaceutically acceptable alcohol is less than or equal to 13%, then the 10 pharmaceutical formulation must comprise at least 50 % non-aqueous ester solvent; and c) if the pharmaceutically acceptable alcohol is greater than 20 % but less than or equal to 25 %, then the pharmaceutical formulation must comprise at least 30 % non-aqueous ester solvent; and also provided that the following pharmaceutical formulation is excluded:
  • a preferred pharmaceutical formulation adapted for intramuscular injection is one 20 comprising 100 mg/ml or more of fulvestrant, 20 % or more weight of a pharmaceutically acceptable alcohol per volume of pharmaceutical formulation, 5 % or more weight of a pharmaceutically acceptable non-aqueous ester solvent per volume of pharmaceutical formulation and 5 % or more weight of ricinoleate excipient per volume of pharmaceutical formulation provided: 25 a) the pharmaceutical formulation comprises at least 10 % weight of ethanol per volume of pharmaceutical formulation; b) if the pharmaceutically acceptable alcohol is 20%), then the pharmaceutical formulation must comprise at least 22.5 % non-aqueous ester solvent; and c) if the pharmaceutically acceptable alcohol is greater than 20 % but less than or equal to 30 25 %>, then the pharmaceutical formulation must comprise at least 15 % non-aqueous ester solvent; and also provided that the following pharmaceutical formulation is excluded: fulvestrant up to
  • a more preferred pharmaceutical formulation adapted for intramuscular injection is one comprising 150 mg/ml or more of fulvestrant, 25 % or more weight of a pharmaceutically acceptable alcohol per volume of pharmaceutical formulation, 30 % or more weight of a pharmaceutically acceptable non-aqueous ester solvent per volume of pharmaceutical formulation and 5 % or more weight of ricinoleate excipient per volume of pharmaceutical formulation provided: a) the pharmaceutical formulation comprises at least 10 % weight of ethanol per volume of pharmaceutical formulation; b) if the pharmaceutically acceptable alcohol is less than 30 %, then the pharmaceutical formulation must comprise at least 35 % non-aqueous ester solvent.
  • a particularly preferred pharmaceutical formulation is one which comprises 15% w/v or less of ethanol and in which the solubility of fulvestrant is at least 155mg/ml.
  • a unit dose of a pharmaceutical formulation as described herein wherein the total volume of the formulation is 6ml or less.
  • a pharmaceutical formulation adapted for intramuscular injection as defined in any preceding claim for use in medical therapy.
  • fulvestrant in the preparation of a pharmaceutical formulation, as defined herein for the treatment of a benign or malignant disease of the breast or reproductive tract.
  • a sterile syringe or vial comprising a pharmaceutical formulation as defined in any preceding claim.
  • pharmaceutical formulation means the combination of drug plus formulation vehicle.
  • finished formulation and “finished pharmaceutical formulation” mean the same as “pharmaceutical formulation”.
  • formulation vehicle means the combination of all excipients used in the pharmaceutical formulation (and therefore excludes drug per se).
  • composition is important for the following reason. For example, if the concentration (y % w/v) of an excipient "A" is measured by its concentration in formulation vehicle and then drug is added, the addition of drug will result in a concentration of excipient A that is lower than concentration y in the finished pharmaceutical formulation.
  • concentration expressed in terms of "formulation vehicle” into a concentration of "finished pharmaceutical formulation” it is necessary to use a displacement value.
  • the "displacement value” is defined as the number of parts by weight of compound that displaces one part by weight of the formulation vehicle.
  • the displacement value allows determination of the amount of formulation vehicle displaced by the compound.
  • the displacement value is used to calculate the actual composition of the finished formulation in terms of proportions of excipients.
  • the density of the compound affects the amount of formulation vehicle required to make the pharmaceutical formulation to the correct concentration.
  • One part by weight of the compound with a density equal to the formulation vehicle will displace an equivalent volume of the formulation vehicle.
  • a compound with twice the density of the formulation vehicle will displace half the volume. It is therefore necessary to make allowance for the compound in terms of the particular formulation vehicle, using the displacement value.
  • %> weight per volume of formulation for the constituents of the formulation we mean that within a unit volume of the formulation a certain percentage of the constituent by weight will be present, for example a 1% weight per volume formulation will contain within a 100ml volume of formulation lg of the constituent.
  • the formulation will be presented in a vial or a prefilled syringe, preferably a prefilled syringe, containing a unit dosage of the formulation as described herein, these being further features of the invention.
  • the pharmaceutically-acceptable alcohol may consist of one alcohol or a mixture of two or more alcohols, preferably a mixture of two alcohols.
  • Preferred pharmaceutically- acceptable alcohols for parenteral administration are ethanol, benzyl alcohol or a mixture of both ethanol and benzyl alcohol.
  • the pharmaceutically-acceptable non-aqueous ester solvent may consist of one or a mixture of two or more pharmaceutically-acceptable non-aqueous ester solvents, preferably just one.
  • a preferred pharmaceutically-acceptable non-aqueous ester solvent for parenteral administration is selected from benzyl benzoate, ethyl oleate, isopropyl myristate, isopropyl palmitate or a mixture of any thereof.
  • the pharmaceutically-acceptable alcohol will be of a quality such that it will meet pharmacopoeial standards (such as are described in the US, British, European and Japanese pharmacopoeias) and as such will contain some water and possibly other organic solvents, for example ethanol in the US Pharmacopeia contains not less than 94.9% by volume and not more than 96.0% by volume of ethanol when measured at 15.56°C. Dehydrated alcohol in the US Pharmacopeia contains not less than 99.5%) ethanol by volume when measured at 15.56°C.
  • the pharmaceutically-acceptable non- aqueous ester solvent will be of a quality that it will meet pharmacopoeial standards (such as described in the US, British, European and Japanese pharmacopoeias).
  • ricinoleate excipient we mean an oil which has as a proportion
  • the ricinoleate vehicle may be a synthetic oil or conveniently is castor oil, ideally of pharmacopoeial standards, as described above.
  • extended release we mean at least 4 weeks, at least 5 weeks, and, preferably at least 8 weeks of continuous release of fulvestrant is achieved. In a preferred feature extended release is achieved for at least 8 weeks or 2 months, more preferably for at least 12 weeks or 3 months.
  • Preferably 5ml of the intramuscular injection is administered.
  • Additional excipients commonly used in the formulation field including, for example, an antioxidant preservative, a colorant or a surfactant may be used.
  • a preferred optional excipient is a surfactant, more preferably an antioxidant.
  • fulvestrant is useful in the treatment of oestrogen-dependent indications such as breast cancer and gynaecological conditions, such as endometriosis.
  • oestrogen-dependent indications such as breast cancer and gynaecological conditions, such as endometriosis.
  • SH-646 l l ⁇ -fluoro- 7 ⁇ -(14,14,15,15,15-pentafluoro-6- methyl-10-thia-6-azapentadecyl)estra-l ,3,5(10)-triene-3,17 ⁇ -diol
  • SH-646 l l ⁇ -fluoro- 7 ⁇ -(14,14,15,15,15-pentafluoro-6- methyl-10-thia-6-azapentadecyl)estra-l ,3,5(10)-triene-3,17 ⁇ -diol
  • Wakeling AE Therapeutic potential of pure antioestrogens in the treatment of breast cancer. Journal Steroid Biochemistry 1990c; 37: 771-5. 5. Wakeling AE, Bowler J. Steroidal pure antioestrogens. Journal Endocrinology 1987; 1 12: R7-10.
  • Figure 1 shows plasma profiles obtained following IM injection (data normalised for rabbit weight, based on 3.2 kg rabbit) in which the y-axis is cone (ng/ml) and the x-axis is time (days);
  • Figure 2 shows comparison of plasma profiles in which:
  • Figure 2A shows plasma profiles from group A in which the y-axis is cone (ng/ml) and the x-axis is time (days);
  • Figure 2B shows plasma profiles from group B in which the y-axis is cone (ng/ml) and the x-axis is time (days);
  • Figure 3 shows plasma profiles from formulations 1 , 5 and Control (normalised for rabbit weight, based on 3.2 kg rabbit in which the y-axis is cone (ng/ml) and the x-axis is time (days);
  • Figure 4 shows muscle residue data from 3 month PK study in which the y-axis is %> fulvestrant remaining per injection site and the x-axis is formulation number. Each bar represents one injection site (2 sites per animal).
  • Figure 5 shows predicted versus actual solubility
  • Figure 6 shows a confidence interval for predicted solubility
  • Figure 7 shows plasma profiles obtained following IM injection (data normalised for rabbit weight, based on 3.2 kg rabbit) in which the y-axis is cone (ng/ml) and the x- axis is time (days);
  • PDP Positive displacement pipette
  • 2.1 1ml formulation vehicles were made up in triplicate by adding the appropriate volumes of alcohols and benzyl benzoate, and then adding castor oil by weight 2.2 Fulvestrant was then added to excess, until no more drug was seen to visibly dissolve. The weight of fulvestrant added was noted.
  • amber vials were capped, vortex mixed for 10 seconds, sonicated for 10 minutes and then placed in the HPLC autosampler tray.
  • Fulvestrant is mixed with ethanol and benzyl alcohol, stirring until completely dissolved. Benzyl benzoate is added and the solution is made to final weight with castor oil and stirred, (for convenience weight is used rather than volume by using the weight to volume ratio).
  • the bulk solution is overlaid with nitrogen.
  • the solution is sterilised by filtration using one or two filters of 0.2 ⁇ m porosity.
  • the sterile filtrate is kept under a nitrogen overlay as it is filled under aseptic conditions into washed and depyrogenised, sterile primary containers, for example vials or pre-filled syringes. An overage is included in the primary pack to 5 facilitate removal of the dose volume.
  • the primary packs are overlaid with sterile nitrogen, before aseptically sealing.
  • the process flow diagram below depicts the manufacturing process.
  • Fulvestrant STAGE 1 DISSOLUTION OF Alcohol ACTIVE AGENT Benzyl Alcohol
  • Control Sample refers to the following Pharmaceutical formulation: fulvestrant 50mg/ml, ethanol 10% w/v, benzylalcohol 10% w/v, benzyl benzoate 15% w/v and made to volume with castor oil.
  • a matrix of 7 pharmaceutical formulations (samples 3, 4, 5, 9, 12, 14 and 16 - see Example 3 below) was identified for further evaluation from in vitro precipitation and deposition studies.
  • Sample 16 was a control.
  • the precipitation experiment involved visual inspection of each sample under conditions where evaporation of alcohols led to precipitation of drug.
  • Tables below show predicted formulations for various solubilities of fulvestrant; where an "X" means in solution. Note that the Tables include some impractical formulations where the sum of components becomes greater than 100%.
  • the principal purpose is to illustrate the wide combinations of ethanol/ benzyl alcohol / benzyl benzoate taught by the invention to achieve different solubilities of fulvestrant.
  • Formulations F3 and F6 as described in Example 4 were modified to contain an increased level of fulvestrant to 140mg/ml.
  • the modified formulations were named F8 and F9 as described below.
  • compositions of the formulations dosed in the PK study are shown in the table below.
  • composition of the Control is the same as described in Example 4.
  • Compositions F8 and F9 gave similar profiles with improved performance in terms of extended release of higher levels fulvestrant compared with Control.
  • compositions analogous or similar to F3, F4, F5 and F6 (see Example 4) but comprising 150mg/ml of fulvestrant are prepared as follows.

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Abstract

The invention relates to a sustained release pharmaceutical formulation adapted for administration by injection containing the compound fulvestrant, 7 a-[9-(4,4,5,5,5-pentafluoropentylsulphiny1)nony1]oestra-1,3,5(10)-triene-3,17 ß-diol, at concentration of at least 100mg/ml in solution in a ricinoleate vehicle which additionally comprises at least one alcohol and a non-aqueous ester solvent which is miscible in the ricinoleate vehicle.

Description

PHARMACEUTICAL FORMULATION FOR THE INTRAMUSCULAR ADMINISTRATION OF FULVESTRANT
The invention relates to a sustained release pharmaceutical formulation adapted for administration by injection containing the compound fulvestrant, 7α-[9-(4,4, 5,5,5- 5 pentafluoropentylsulphinyl)nonyl]oestra-l,3,5(10)-triene-3,17β-diol, at concentration of at least lOOmg/ml in solution in a ricinoleate vehicle which additionally comprises at least one alcohol and a non-aqueous ester solvent which is miscible in the ricinoleate vehicle.
Oestrogen deprivation is fundamental to the treatment of many benign and malignant diseases of the breast and reproductive tract. In premenopausal women, this is achieved by 0 the ablation of ovarian function through surgical, radiotherapeutic, or medical means, and, in postmenopausal women, by the use of aromatase inhibitors.
An alternative approach to oestrogen withdrawal is to antagonise oestrogens with antioestrogens. These are drugs that bind to and compete for oestrogen receptors (ER) present in the nuclei of oestrogen-responsive tissue. Conventional nonsteroidal antioestrogens, such 5 as tamoxifen, compete efficiently for ER binding but their effectiveness is often limited by the partial agonism they display, which results in an incomplete blockade of oestrogen-mediated activity (Furr and Jordan, Pharmacology & Therapeutics, 25: 127-206, 1984; May and
Westley, J Biol Chem 262:15894-15899, 1987).
The potential for nonsteroidal antioestrogens to display agonistic properties prompted 0 the search for novel compounds that would bind ER with high affinity without activating any of the normal transcriptional hormone responses and consequent manifestations of oestrogens.
Such molecules would be "pure" antioestrogens, clearly distinguished from tamoxifen-like ligands and capable of eliciting complete ablation of the trophic effects of oestrogens. Such compounds are referred to as Estrogen Receptor-Downregulators (E.R.D.). The rationale for 5 the design and testing of novel, pure antioestrogens has been described in: Bowler et al 1989,
Wakeling 1990a, 1990b, 1990c. Wakeling and Bowler 1987, 1988.
Steroidal analogues of oestradiol, with an alkylsulphinyl side chain in the 7α position, provided the first examples of compounds devoid of oestrogenic activity (Bowler et al 1989).
One of these, 7α-[9-(4,4,5,5,5-pentafluoropentyl sulphinyl)nonyl]oestra-l,3,5-(10)triene- 0 3,17β-diol was selected for intensive study on the basis of its pure oestrogen antagonist activity and significantly increased antioestrogenic potency over other available antioestrogens. In vitro findings and early clinical experience with 7α-[9-(4,4,5,5,5-pentafluoropentylsulphinyl)nonyl]oestra- 1 ,3-5(10)-triene-3, 17β-diol have promoted interest in the development of the drug as a therapeutic agent for oestrogen- dependent indications such as breast cancer and certain benign gynaecological conditions.
7α-[9-(4,4,5,5,5-Pentafluoropentylsulρhinyl)nonyl]oestra-l,3-5(10)-triene-3,17β-diol, or ICI 182,780, has been allocated the international non-proprietary name fulvestrant, which is used hereinafter. When referring to fulvestrant we include pharmaceutically-acceptable salts thereof and any possible solvates of either thereof.
Fulvestrant binds to ER with an affinity similar to that of oestradiol and completely blocks the growth stimulatory action of oestradiol on human breast cancer cells in vitro; it is more potent and more effective than tamoxifen in this respect. Fulvestrant blocks completely the uterotrophic action of oestradiol in rats, mice and monkeys, and also blocks the uterotrophic activity of tamoxifen.
Because fulvestrant has none of the oestrogen-like stimulatory activity that is characteristic of clinically available antioestrogens such as tamoxifen or toremifene, it may offer improved therapeutic activity characterised by more rapid, complete, or longer-lasting tumour regression; a lower incidence or rate of development of resistance to treatment; and a reduction of tumour invasiveness.
In intact adult rats, fulvestrant achieves maximum regression of the uterus at a dose which does not adversely affect bone density or lead to increased gonadotrophin secretion. If also true in humans, these findings could be of extreme importance clinically. Reduced bone density limits the duration of oestrogen-ablative treatment for endometriosis. Fulvestrant does not block hypothalamic ER. Oestrogen ablation also causes or exacerbates hot flushes and other menopausal symptoms; fulvestrant will not cause such effects because it does not cross the blood-brain barrier. European Patent Application No. 0 138 504 discloses that certain steroid derivatives are effective antioestrogenic agents. The disclosure includes information relating to the preparation of the steroid derivatives. In particular there is the disclosure within Example 35 of the compound 7α-[9-(4,4,5,5,5-pentafluoropentylsulphinyl)nonyl]oestra- 1,3,5(10)-triene-3 , 17β-diol, which compound is specifically named in Claim 4. It is also disclosed that the compounds of that invention may be provided for use in the form of a pharmaceutical composition comprising a steroid derivative of the invention together with a pharmaceutically-acceptable diluent or carrier. It is stated therein that the composition can be in a form suitable for oral or parenteral administration.
Fulvestrant shows, along with other steroidal based compounds, certain physical properties which make formulation of these compounds difficult. Fulvestrant is a particularly lipophilic molecule, even when compared with other steroidal compounds, and its aqueous solubility is extremely low at around 10 ngml'1 (this is an estimate from a water/solvent mixture solute since measurements this low could not be achieved in a water only solute). Currently there are a number of sustained release injectable steroidal formulations which have been commercialised. Commonly these formulations use oil as a solvent and wherein additional excipients may be present.
In US 5,183,814 Example 3 an oil based injection formulation of fulvestrant is described which comprises 50mg of fulvestrant, 400mg of benzyl alcohol and sufficient castor oil to bring the solution to a volume of 1 ml. Manufacture at a commercial scale of a formulation as described in US 5,183,814 will be complicated by the high alcohol concentration. Therefore, there is a need to lower the alcohol concentration in fulvestrant formulations whilst preventing precipitation of fulvestrant from the formulation.
The Table below shows the solubility of fulvestrant in a number of different solvents.
SOLUBILITY OF FULVESTRANT
SOLVENT SOLUBILITY
(mgml-1 at 25°C)
Water 0.001
Arachis oil 0.45
Sesame oil 0.58
Castor oil 20
Miglyol δlO 3.06
Miglyol 812 2.72
Ethyl oleate 1.25
Benzyl benzoate 6.15
Isopropyl myristate 0.80
Span 85 (surfactant) 3.79 Ethanol >200
Benzyl Alcohol >200
As can be seen fulvestrant is significantly more soluble in castor oil than any of the other oils tested. The greater solvating ability of castor oil for steroidal compounds is known and is attributed to the high number of hydroxy groups of ricinoleic acid, which is the major constituent of the fatty acids within the triglycerides present in castor oil - see (Riffkin et.al. J. Pharm. Sci., (1964), 53, 891).
Our earlier application PCT/GBO 1/00049, WO 01/51056, describes certain fulvestrant formulations at a most preferred concentration of 50mg/ml. This application disclosed one formulation with a solubility up to 102 mg/ml - see the last formulation in Table 3 thereof with 15 % weight of ethanol per volume of formulation, 15 % weight of benzyl alcohol per volume of formulation, 15 % weight of benzyl benzoate per volume of formulation in a ricinoleate vehicle. However there is a need for further formulations of fulvestrant that contain high concentrations of fulvestrant to facilitate administration thereof at higher doses or less frequent intervals. According to another aspect of the invention there is provided a pharmaceutical formulation adapted for intramuscular injection comprising 100 mg/ml or more of fulvestrant, 10 % or more weight of a pharmaceutically acceptable alcohol per volume of formulation vehicle, 5 % or more weight of a pharmaceutically acceptable non-aqueous ester solvent per volume of formulation vehicle and 5 % or more weight of ricinoleate excipient per volume of formulation vehicle provided the formulation vehicle comprises at least 5 % weight of ethanol per volume of formulation vehicle and provided that the following formulation is excluded: fulvestrant up to 102 mg/ml, 15 % weight of ethanol per volume of formulation vehicle, 15 % weight of benzyl alcohol per volume of formulation vehicle, 15 % weight of benzyl benzoate per volume of formulation vehicle and 30 % or more weight of ricinoleate excipient per volume of formulation vehicle.
A preferred pharmaceutical formulation adapted for intramuscular injection is one comprising 105 mg/ml or more of fulvestrant, 10 % or more weight of a pharmaceutically acceptable alcohol per volume of formulation vehicle, 5 % or more weight of a pharmaceutically acceptable non-aqueous ester solvent per volume of formulation vehicle and 5 % or more weight of ricinoleate excipient per volume of formulation vehicle provided the formulation comprises at least 5 % weight of ethanol per volume of formulation vehicle. A more preferred pharmaceutical formulation adapted for intramuscular injection is one comprising 110 mg/ml or more of fulvestrant, 10 % or more weight of a pharmaceutically acceptable alcohol per volume of formulation vehicle, 5 % or more weight of a pharmaceutically acceptable non-aqueous ester solvent per volume of formulation vehicle and 5 % or more weight of ricinoleate excipient per volume of formulation vehicle provided the formulation vehicle comprises at least 5 % weight of ethanol per volume of formulation vehicle.
A more preferred pharmaceutical formulation adapted for intramuscular injection is one comprising 1 15 mg/ml or more of fulvestrant, 10 % or more weight of a pharmaceutically acceptable alcohol per volume of formulation vehicle, 5 % or more weight of a pharmaceutically acceptable non-aqueous ester solvent per volume of formulation vehicle and 5 % or more weight of ricinoleate excipient per volume of formulation vehicle provided the formulation vehicle comprises at least 5 % weight of ethanol per volume of formulation vehicle. A more preferred pharmaceutical formulation adapted for intramuscular injection is one comprising 120 mg/ml or more of fulvestrant, 10 % or more weight of a pharmaceutically acceptable alcohol per volume of formulation vehicle, 5 % or more weight of a pharmaceutically acceptable non-aqueous ester solvent per volume of formulation vehicle and 5 % or more weight of ricinoleate excipient per volume of formulation vehicle provided the formulation vehicle comprises at least 5 % weight of ethanol per volume of formulation vehicle.
A more preferred pharmaceutical formulation adapted for intramuscular injection is one comprising 130 mg/ml or more of fulvestrant, 15 % or more weight of a pharmaceutically acceptable alcohol per volume of formulation vehicle, 5 % or more weight of a pharmaceutically acceptable non-aqueous ester solvent per volume of formulation vehicle and 5 % or more weight of ricinoleate excipient per volume of formulation vehicle provided the formulation vehicle comprises at least 5 % weight of ethanol per volume of formulation vehicle.
A more preferred pharmaceutical formulation adapted for intramuscular injection is one comprising 140 mg/ml or more of fulvestrant, 15 % or more weight of a pharmaceutically acceptable alcohol per volume of formulation vehicle, 12.5 % or more weight of a pharmaceutically acceptable non-aqueous ester solvent per volume of formulation vehicle and 5 % or more weight of ricinoleate excipient per volume of formulation vehicle provided the formulation vehicle comprises at least 10 % weight of ethanol per volume of formulation vehicle.
A more preferred pharmaceutical formulation adapted for intramuscular injection is one comprising 150 mg/ml or more of fulvestrant, 15 % or more weight of a pharmaceutically acceptable alcohol per volume of formulation vehicle, 17.5 % or more weight of a pharmaceutically acceptable non-aqueous ester solvent per volume of formulation vehicle and
5 % or more weight of ricinoleate excipient per volume of formulation vehicle provided the formulation vehicle comprises at least 10 % weight of ethanol per volume of formulation vehicle. Another aspect of the invention provides any of the formulations described herein stated as having any minimum ethanol content removed. For example, the formulation described in the paragraph immediately above becomes: a pharmaceutical formulation adapted for intramuscular injection is one comprising 150 mg/ml or more of fulvestrant, 15 % or more weight of a pharmaceutically acceptable alcohol per volume of formulation vehicle, 17.5 % or more weight of a pharmaceutically acceptable non-aqueous ester solvent per volume of formulation vehicle and 5 % or more weight of ricinoleate excipient per volume of formulation vehicle.
According to another aspect of the invention there is provided a pharmaceutical formulation having a solubility for fulvestrant of at least Y mg/ml adapted for intramuscular injection comprising;
100 mg/ml or more of fulvestrant;
5% (w/v) or more castor oil per volume of formulation vehicle; and at least the following amounts (% weight/volume of formulation vehicle) of ethanol
(ETOH), benzyl alcohol (BA), benzyl benzoate (BB) determined by the algorithm: Y = -29.77 + 5.44 x ETOH + 2.38 x BA + 1.57 x BB wherein x is at least 100, ETOH is at least 5, BA is at least 5 and BB is at least 5.
A preferred pharmaceutical formulation is one wherein Y is selected from the group consisting of 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 170, 180, 190, and
200. A more preferred pharmaceutical formulation is one wherein Y is selected from the group consisting of 120, 125, 130, 135, 140, 145, 150, 155, 160, 170, 180, 190, and 200. A more preferred pharmaceutical formulation is one wherein Y is selected from the group consisting of 150, 155, 160, 170, 180, 190 and 200. A more preferred pharmaceutical formulation is one wherein Y is selected from 150, 155, 160, 170, 180, 190 and 200 and the formulation comprises at least 150mg/ml of fulvestrant.
A more preferred pharmaceutical formulation is one wherein Y is 200 and the formulation comprises at least 200mg/ml of fulvestrant.
According to another aspect of the present invention there is provided a pharmaceutical formulation having a solubility for fulvestrant of at least 100 mg/ml adapted for intramuscular injection comprising; 100 mg/ml or more of fulvestrant; 5% (w/v) or more castor oil per volume of formulation vehicle; and at least the following amounts (% weight/volume of formulation vehicle) of ethanol (EtOH), benzyl alcohol (BA), benzyl benzoate (BB) determined by the algorithm: 100 = -29.77 + 5.44 x ETOH + 2.38 x BA + 1.57 x BB; and provided that the following formulation is excluded: fulvestrant up to 102 mg/ml, 15 % weight of ethanol per volume of formulation vehicle, 15 % weight of benzyl alcohol per volume of formulation vehicle, 15 % weight of benzyl benzoate per volume of formulation vehicle and 30 % or more weight of castor oil per volume of formulation vehicle.
According to another aspect of the invention there is provided a pharmaceutical formulation comprising fulvestrant at a concentration of at least 100 mg/ml in which the formulation is adapted for intra-muscular injection into a human and which is capable after injection of attaining a therapeutically significant blood plasma fulvestrant concentration in a human for at least 2 months and provided that the following formulation is excluded: fulvestrant up to 102 mg/ml, 15 % weight of ethanol per volume of formulation vehicle, 15 % weight of benzyl alcohol per volume of formulation vehicle, 15 % weight of benzyl benzoate per volume of formulation vehicle and 30 % or more weight of ricinoleate excipient per volume of formulation vehicle.
According to another aspect of the invention there is provided a pharmaceutical formulation comprising fulvestrant in which the formulation is adapted for intra-muscular injection into a human and which is capable after injection of attaining a therapeutically significant blood plasma fulvestrant concentration in a human for at least 2 months.
According to another aspect of the invention there is provided a pharmaceutical formulation comprising fulvestrant at a concentration of at least 100 mg/ml in which the formulation is adapted for intra-muscular injection into a human and which is capable after injection of attaining a therapeutically significant blood plasma fulvestrant concentration in a human for at least 2 months.
According to another aspect of the invention there is provided a pharmaceutical formulation comprising fulvestrant at a concentration of at least 150 mg/ml in which the 5 formulation is adapted for intra-muscular injection into a human and which is capable after injection of attaining a therapeutically significant blood plasma fulvestrant concentration in a human for at least 2 months.
According to another aspect of the invention there is provided a pharmaceutical formulation comprising fulvestrant at a concentration of at least 200 mg/ml in which the 10 formulation is adapted for intra-muscular injection into a human and which is capable after injection of attaining a therapeutically significant blood plasma fulvestrant concentration in a human for at least 2 months.
According to another aspect of the invention there is provided a pharmaceutical formulation comprising fulvestrant at a concentration of at least 300 mg/ml in which the 15 formulation is adapted for intra-muscular injection into a human and which is capable after injection of attaining a therapeutically significant blood plasma fulvestrant concentration in a human for at least 2 months.
According to one aspect of the invention there is provided any one of the following pharmaceutical formulations comprising about: 20 i)
10% weight per volume of ethanol
20% weight per volume of benzyl alcohol
15% weight per volume of benzyl benzoate
500-555mg of fulvestrant for each 5ml of finished formulation 25 and the remaining amount as castor oil; ϋ)
10% weight per volume of ethanol 20%) weight per volume of benzyl alcohol 30% weight per volume of benzyl benzoate 30 500-700mg of fulvestrant for each 5ml of finished formulation and the remaining amount as castor oil; iϋ)
10% weight per volume of ethanol 20% weight per volume of benzyl alcohol 50% weight per volume of benzyl benzoate 500-750mg of fulvestrant for each 5ml of finished formulation and the remaining amount as castor oil; 5 iv)
20% weight per volume of ethanol 20% weight per volume of benzyl alcohol 30% weight per volume of benzyl benzoate 500-1175mg of fulvestrant for each 5ml of finished formulation 10 and the remaining amount as castor oil; v)
15% weight per volume of ethanol 10% weight per volume of benzyl alcohol 50% weight per volume of benzyl benzoate 15 500-810 mg of fulvestrant for each 5ml of finished formulation and the remaining amount as castor oil; vi)
15% weight per volume of ethanol
20% weight per volume of benzyl alcohol 20 50% weight per volume of benzyl benzoate
500 mg of fulvestrant for each 5ml of finished formulation and the remaining amount as castor oil; vii)
15% weight per volume of ethanol 25 20% weight per volume of benzyl alcohol
30% weight per volume of benzyl benzoate
500-630mg of fulvestrant for each 5ml of finished formulation and the remaining amount as castor oil; viii) 30 10% weight per volume of ethanol
20% weight per volume of benzyl alcohol
50% weight per volume of benzyl benzoate
750mg of fulvestrant for each 5ml of finished formulation and the remaining amount as castor oil; ix)
20% weight per volume of ethanol 20% weight per volume of benzyl alcohol 5 30% weight per volume of benzyl benzoate
750mg of fulvestrant for each 5ml of finished formulation and the remaining amount as castor oil; x)
15% weight per volume of ethanol
10 10% weight per volume of benzyl alcohol
50% weight per volume of benzyl benzoate
750mg of fulvestrant for each 5ml of finished formulation and the remaining amount as castor oil; xi) 15 9% weight per volume of ethanol
19% weight per volume of benzyl alcohol
47% weight per volume of benzyl benzoate
700mg of fulvestrant for each 5ml of finished formulation and the remaining amount as castor oil; 20 xii)
14% weight per volume of ethanol
19% weight per volume of benzyl alcohol
48% weight per volume of benzyl benzoate
700mg of fulvestrant for each 5ml of finished formulation 25 and the remaining amount as castor oil; xiii)
15% weight per volume of ethanol
20% weight per volume of benzyl alcohol
45% weight per volume of benzyl benzoate 30 750mg of fulvestrant for each 5ml of finished formulation and the remaining amount as castor oil; xiv)
9% weight per volume of ethanol 19% weight per volume of benzyl alcohol
47% weight per volume of benzyl benzoate
750mg of fulvestrant for each 5ml of finished formulation and the remaining amount as castor oil; 5 xv)
19% weight per volume of ethanol
19% weight per volume of benzyl alcohol
28% weight per volume of benzyl benzoate
750mg of fulvestrant for each 5ml of finished formulation 10 and the remaining amount as castor oil; xvi)
14% weight per volume of ethanol
9% weight per volume of benzyl alcohol
47% weight per volume of benzyl benzoate 15 750mg of fulvestrant for each 5ml of finished formulation and the remaining amount as castor oil; xvii)
14% weight per volume of ethanol
19% weight per volume of benzyl alcohol 20 47% weight per volume of benzyl benzoate
750mg of fulvestrant for each 5ml of finished formulation and the remaining amount as castor oil; xviii)
10% weight per volume of ethanol 25 20% weight per volume of benzyl alcohol
45% weight per volume of benzyl benzoate
750mg of fulvestrant for each 5ml of finished formulation and the remaining amount as castor oil; xix) 30 15% weight per volume of ethanol
10% weight per volume of benzyl alcohol
45% weight per volume of benzyl benzoate
750mg of fulvestrant for each 5ml of finished formulation and the remaining amount as castor oil; xx)
20% weight per volume of ethanol
20% weight per volume of benzyl alcohol 5 25% weight per volume of benzyl benzoate
750mg of fulvestrant for each 5ml of finished formulation and the remaining amount as castor oil; xxi)
10% weight per volume of ethanol 10 30%) weight per volume of benzyl alcohol
25% weight per volume of benzyl benzoate
750mg of fulvestrant for each 5ml of finished formulation and the remaining amount as castor oil; xxii) 15 10% weight per volume of ethanol
25% weight per volume of benzyl alcohol
30%) weight per volume of benzyl benzoate
750mg of fulvestrant for each 5ml of finished formulation and the remaining amount as castor oil; 20 xxiii)
10%) weight per volume of ethanol
30%) weight per volume of benzyl alcohol
30%) weight per volume of benzyl benzoate
750mg of fulvestrant for each 5ml of finished formulation 25 and the remaining amount as castor oil; xxiv)
15%) weight per volume of ethanol
25%) weight per volume of benzyl alcohol
30% weight per volume of benzyl benzoate 30 750mg of fulvestrant for each 5ml of finished formulation and the remaining amount as castor oil; xxv)
15%) weight per volume of ethanol 25% weight per volume of benzyl alcohol
25%) weight per volume of benzyl benzoate
750mg of fulvestrant for each 5ml of finished formulation and the remaining amount as castor oil; and xxvi)
15%) weight per volume of ethanol
20% weight per volume of benzyl alcohol
30%) weight per volume of benzyl benzoate
750mg of fulvestrant for each 5ml of finished formulation and the remaining amount as castor oil.
The term "comprising about" in this context means that the numerical value assigned to each component of the formulation may be varied independently to accommodate manufacturing specifications encountered by a skilled person when making up the formulations. Typically this means plus or minus 5%, more preferably plus or minus 4%>, more preferably plus or minus 3%>, more preferably plus or minus 2%, more preferably plus or minus 1%. In a preferred embodiment, more variation in drug level is allowed compared with other components. For example:
Figure imgf000014_0001
The individual formulations described herein may comprise further excipients commonly used in the formulation field including, for example, an antioxidant preservative, a colorant or a surfactant.
According to another aspect of the invention there is provided any one of the following pharmaceutical formulations: i)
10% weight per volume of ethanol
20% weight per volume of benzyl alcohol 15% weight per volume of benzyl benzoate
500-555mg of fulvestrant for each 5ml of finished formulation and the remaining amount as castor oil ϋ) 5 10% weight per volume of ethanol
20% weight per volume of benzyl alcohol
30% weight per volume of benzyl benzoate
500-700mg of fulvestrant for each 5ml of finished formulation and the remaining amount as castor oil 10 iii)
10% weight per volume of ethanol
20% weight per volume of benzyl alcohol
50% weight per volume of benzyl benzoate
500-750mg of fulvestrant for each 5ml of finished formulation 15 and the remaining amount as castor oil iv)
20% weight per volume of ethanol
20% weight per volume of benzyl alcohol
30% weight per volume of benzyl benzoate 20 500- 1175mg of fulvestrant for each 5ml of finished formulation and the remaining amount as castor oil v)
15% weight per volume of ethanol
10% weight per volume of benzyl alcohol 25 50% weight per volume of benzyl benzoate
500-810 mg of fulvestrant for each 5ml of finished formulation and the remaining amount as castor oil vi)
15% weight per volume of ethanol 30 20% weight per volume of benzyl alcohol
50% weight per volume of benzyl benzoate
500 mg of fulvestrant for each 5ml of finished formulation and the remaining amount as castor oil vii)
15% weight per volume of ethanol
20% weight per volume of benzyl alcohol
30% weight per volume of benzyl benzoate 5 500-630mg of fulvestrant for each 5ml of finished formulation and the remaining amount as castor oil viii)
10% weight per volume of ethanol
20% weight per volume of benzyl alcohol 10 50% weight per volume of benzyl benzoate
750mg of fulvestrant for each 5ml of finished formulation and the remaining amount as castor oil ix)
20% weight per volume of ethanol 15 20% weight per volume of benzyl alcohol
30% weight per volume of benzyl benzoate
750mg of fulvestrant for each 5ml of finished formulation and the remaining amount as castor oil x) 20 15% weight per volume of ethanol
10% weight per volume of benzyl alcohol
50% weight per volume of benzyl benzoate
750mg of fulvestrant for each 5ml of finished formulation and the remaining amount as castor oil. 25 A preferred pharmaceutical formulation described herein is one wherein the pharmaceutically-acceptable alcohol is a mixture of ethanol and benzyl alcohol.
A preferred pharmaceutical formulation described herein is one wherein the pharmaceutically-acceptable non-aqueous ester solvent is selected from benzyl benzoate, ethyl oleate, isopropyl myristate, isopropyl palmitate or a mixture of any thereof. 30 A preferred pharmaceutical formulation described herein is one wherein the pharmaceutically-acceptable non-aqueous ester solvent is benzyl benzoate.
A preferred pharmaceutical formulation described herein is one wherein the ricinoleate excipient is castor oil. According to one aspect of the present invention there is provided a pharmaceutical formulation adapted for intramuscular injection comprising 100 mg/ml or more of fulvestrant, 10 %> or more weight of a pharmaceutically acceptable alcohol per volume of pharmaceutical formulation, 5 % or more weight of a pharmaceutically acceptable non-aqueous ester solvent 5 per volume of pharmaceutical formulation and 5 %> or more weight of ricinoleate excipient per volume of pharmaceutical formulation provided: a) the pharmaceutical formulation comprises at least 5 % weight of ethanol per volume of pharmaceutical formulation; b) if the pharmaceutically acceptable alcohol is less than or equal to 13%, then the 10 pharmaceutical formulation must comprise at least 50 % non-aqueous ester solvent; and c) if the pharmaceutically acceptable alcohol is greater than 20 % but less than or equal to 25 %, then the pharmaceutical formulation must comprise at least 30 % non-aqueous ester solvent; and also provided that the following pharmaceutical formulation is excluded: fulvestrant up to 15 102 mg/ml, 15 % weight of ethanol per volume of formulation vehicle, 15 % weight of benzyl alcohol per volume of formulation vehicle, 15 % weight of benzyl benzoate per volume of formulation vehicle and 30 % or more weight of ricinoleate excipient per volume of formulation vehicle.
A preferred pharmaceutical formulation adapted for intramuscular injection is one 20 comprising 100 mg/ml or more of fulvestrant, 20 % or more weight of a pharmaceutically acceptable alcohol per volume of pharmaceutical formulation, 5 % or more weight of a pharmaceutically acceptable non-aqueous ester solvent per volume of pharmaceutical formulation and 5 % or more weight of ricinoleate excipient per volume of pharmaceutical formulation provided: 25 a) the pharmaceutical formulation comprises at least 10 % weight of ethanol per volume of pharmaceutical formulation; b) if the pharmaceutically acceptable alcohol is 20%), then the pharmaceutical formulation must comprise at least 22.5 % non-aqueous ester solvent; and c) if the pharmaceutically acceptable alcohol is greater than 20 % but less than or equal to 30 25 %>, then the pharmaceutical formulation must comprise at least 15 % non-aqueous ester solvent; and also provided that the following pharmaceutical formulation is excluded: fulvestrant up to
102 mg/ml, 15 % weight of ethanol per volume of formulation vehicle, 15 % weight of benzyl alcohol per volume of formulation vehicle, 15 % weight of benzyl benzoate per volume of formulation vehicle and 30 % or more weight of ricinoleate excipient per volume of formulation vehicle.
A more preferred pharmaceutical formulation adapted for intramuscular injection is one comprising 150 mg/ml or more of fulvestrant, 25 % or more weight of a pharmaceutically acceptable alcohol per volume of pharmaceutical formulation, 30 % or more weight of a pharmaceutically acceptable non-aqueous ester solvent per volume of pharmaceutical formulation and 5 % or more weight of ricinoleate excipient per volume of pharmaceutical formulation provided: a) the pharmaceutical formulation comprises at least 10 % weight of ethanol per volume of pharmaceutical formulation; b) if the pharmaceutically acceptable alcohol is less than 30 %, then the pharmaceutical formulation must comprise at least 35 % non-aqueous ester solvent.
A particularly preferred pharmaceutical formulation is one which comprises 15% w/v or less of ethanol and in which the solubility of fulvestrant is at least 155mg/ml.
According to another aspect of the invention there is provided a unit dose of a pharmaceutical formulation as described herein wherein the total volume of the formulation is 6ml or less.
According to another aspect of the invention there is provided a pharmaceutical formulation adapted for intramuscular injection, as defined in any preceding claim for use in medical therapy.
According to another aspect of the invention there is provided use of fulvestrant in the preparation of a pharmaceutical formulation, as defined herein for the treatment of a benign or malignant disease of the breast or reproductive tract. According to another aspect of the invention there is provided use of fulvestrant in the preparation of a pharmaceutical formulation, as defined in any preceding claim for the treatment of a benign or malignant disease of the breast or reproductive tract in a human with dosage intervals of at least 8 weeks.
According to another aspect of the invention there is provided a sterile syringe or vial comprising a pharmaceutical formulation as defined in any preceding claim.
The term "pharmaceutical formulation" as used herein means the combination of drug plus formulation vehicle. The terms "finished formulation" and "finished pharmaceutical formulation" mean the same as "pharmaceutical formulation". The term "formulation vehicle" as used herein means the combination of all excipients used in the pharmaceutical formulation (and therefore excludes drug per se).
The distinction between pharmaceutical formulation and formulation vehicle is important for the following reason. For example, if the concentration (y % w/v) of an excipient "A" is measured by its concentration in formulation vehicle and then drug is added, the addition of drug will result in a concentration of excipient A that is lower than concentration y in the finished pharmaceutical formulation. To convert a concentration expressed in terms of "formulation vehicle" into a concentration of "finished pharmaceutical formulation" it is necessary to use a displacement value. The "displacement value" is defined as the number of parts by weight of compound that displaces one part by weight of the formulation vehicle. The displacement value allows determination of the amount of formulation vehicle displaced by the compound. The displacement value is used to calculate the actual composition of the finished formulation in terms of proportions of excipients. The density of the compound affects the amount of formulation vehicle required to make the pharmaceutical formulation to the correct concentration. One part by weight of the compound with a density equal to the formulation vehicle will displace an equivalent volume of the formulation vehicle. A compound with twice the density of the formulation vehicle will displace half the volume. It is therefore necessary to make allowance for the compound in terms of the particular formulation vehicle, using the displacement value.
For the avoidance of any doubt when using the term %> weight per volume of formulation for the constituents of the formulation we mean that within a unit volume of the formulation a certain percentage of the constituent by weight will be present, for example a 1% weight per volume formulation will contain within a 100ml volume of formulation lg of the constituent. By way of further illustration
Figure imgf000019_0001
Where whole numbers are used for % weight per volume of formulation, these refer to rounded numbers where appropriate. For example, 4.6% would be rounded to 5%.
It is appreciated that in the formulation an excess of formulation may be included to allow the attendant physician or care giver to be able to deliver the required dose. Therefore, when a 5ml dose is required it would be appreciated that an excess of up to 0.25ml, preferably up to 0.15ml will also be present in the formulation. Typically the formulation will be presented in a vial or a prefilled syringe, preferably a prefilled syringe, containing a unit dosage of the formulation as described herein, these being further features of the invention.
The pharmaceutically-acceptable alcohol may consist of one alcohol or a mixture of two or more alcohols, preferably a mixture of two alcohols. Preferred pharmaceutically- acceptable alcohols for parenteral administration are ethanol, benzyl alcohol or a mixture of both ethanol and benzyl alcohol.
The pharmaceutically-acceptable non-aqueous ester solvent may consist of one or a mixture of two or more pharmaceutically-acceptable non-aqueous ester solvents, preferably just one. A preferred pharmaceutically-acceptable non-aqueous ester solvent for parenteral administration is selected from benzyl benzoate, ethyl oleate, isopropyl myristate, isopropyl palmitate or a mixture of any thereof.
It will be understood by the skilled person that the pharmaceutically-acceptable alcohol will be of a quality such that it will meet pharmacopoeial standards (such as are described in the US, British, European and Japanese pharmacopoeias) and as such will contain some water and possibly other organic solvents, for example ethanol in the US Pharmacopeia contains not less than 94.9% by volume and not more than 96.0% by volume of ethanol when measured at 15.56°C. Dehydrated alcohol in the US Pharmacopeia contains not less than 99.5%) ethanol by volume when measured at 15.56°C. It will be understood by the skilled person that the pharmaceutically-acceptable non- aqueous ester solvent will be of a quality that it will meet pharmacopoeial standards (such as described in the US, British, European and Japanese pharmacopoeias).
Preferred combinations of pharmaceutically-acceptable alcohol and pharmaceutically- acceptable non-aqueous ester solvent in the formulation are set out below: By the use of the term ricinoleate excipient we mean an oil which has as a proportion
(at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 95% w/v) of its composition as triglycerides of ricinoleic acid. The ricinoleate vehicle may be a synthetic oil or conveniently is castor oil, ideally of pharmacopoeial standards, as described above.
We have surprisingly found that the above formulations of the invention provide, after intra-muscular injection, satisfactory release of fulvestrant over an extended period of time. We have found that despite the rapid elimination of the additional solubilising excipients, i.e. the alcohol and pharmaceutically-acceptable non-aqueous ester solvent, from the formulation vehicle and the site of injection after injection of the formulation, extended release at therapeutically significant levels of fulvestrant over an extended period can still achieved by the formulation of the invention. By use of the term "extended release" we mean at least 4 weeks, at least 5 weeks, and, preferably at least 8 weeks of continuous release of fulvestrant is achieved. In a preferred feature extended release is achieved for at least 8 weeks or 2 months, more preferably for at least 12 weeks or 3 months.
It will be understood that the attendant physician may wish to administer the intramuscular injection as a divided dose, i.e. a 5ml formulation is sequentially administered in two separate injections of 2.5ml, this is a further feature of the invention
Simply solubilising fulvestrant in an oil based liquid formulation is not predictive of a good release profile.
Preferably 5ml of the intramuscular injection is administered. Additional excipients commonly used in the formulation field including, for example, an antioxidant preservative, a colorant or a surfactant may be used. A preferred optional excipient is a surfactant, more preferably an antioxidant.
As described above fulvestrant is useful in the treatment of oestrogen-dependent indications such as breast cancer and gynaecological conditions, such as endometriosis. In addition to fulvestrant another similar type of molecule is currently under clinical investigation. SH-646 (l l β-fluoro- 7α-(14,14,15,15,15-pentafluoro-6- methyl-10-thia-6-azapentadecyl)estra-l ,3,5(10)-triene-3,17β-diol) is also putatively a compound with the same mode of action as fulvestrant and has a very similar chemical structure. It is believed that the compound will also share with fulvestrant similar physical properties and therefore the current invention will also have application with this compound.
Further features of the invention are those as described above but in which SH-646 is substituted for fulvestrant. References
1. Bowler J, Lilley TJ, Pittam JD, Wakeling AE. Novel steroidal pure antioestrogens. Steroids, 54: 71-100, 1989.
2. Wakeling AE. Novel pure antioestrogens: mode of action and therapeutic prospects. American New York Academy Science 1990a; 595: 348-56.
3. Wakeling AE. Steroidal pure antioestrogens. In Lippman M, Dickson R, editors. Regulatory mechanisms in breast cancer. Boston: Kluwer Academic, 1990b: 239-57.
4. Wakeling AE. Therapeutic potential of pure antioestrogens in the treatment of breast cancer. Journal Steroid Biochemistry 1990c; 37: 771-5. 5. Wakeling AE, Bowler J. Steroidal pure antioestrogens. Journal Endocrinology 1987; 1 12: R7-10.
6. Wakeling AE, Bowler J. Biology and mode of action of pure antioestrogens. Journal Steroid Biochemistry 1988; 3: 141-7.
The invention will now be illustrated by the following non-limiting Examples in which:
Figure 1 shows plasma profiles obtained following IM injection (data normalised for rabbit weight, based on 3.2 kg rabbit) in which the y-axis is cone (ng/ml) and the x-axis is time (days); Figure 2 shows comparison of plasma profiles in which:
Figure 2A shows plasma profiles from group A in which the y-axis is cone (ng/ml) and the x-axis is time (days); and
Figure 2B shows plasma profiles from group B in which the y-axis is cone (ng/ml) and the x-axis is time (days); Figure 3 shows plasma profiles from formulations 1 , 5 and Control (normalised for rabbit weight, based on 3.2 kg rabbit in which the y-axis is cone (ng/ml) and the x-axis is time (days); Figure 4 shows muscle residue data from 3 month PK study in which the y-axis is %> fulvestrant remaining per injection site and the x-axis is formulation number. Each bar represents one injection site (2 sites per animal).
Figure 5 shows predicted versus actual solubility Figure 6 shows a confidence interval for predicted solubility Figure 7 shows plasma profiles obtained following IM injection (data normalised for rabbit weight, based on 3.2 kg rabbit) in which the y-axis is cone (ng/ml) and the x- axis is time (days);
Abbreviations IM intramuscular
PK pharmacokinetic
AUC area under curve
SD standard deviation
Reference Example 1
Measurement of Solubility of Fulvestrant in Formulations 1. Materials and Apparatus Balance
2 mL glass vials with screw caps Magnetic stirrer bars
Temperature control reaction block with magnetic stirring facility
Positive displacement pipette (PDP) 20 - 25 μL with appropriate microsyringe tips
Polycarbonate ultracentrifuge tubes
Ultracentrifuge Pipette 0.5 - 200 μL PDP with appropriate microsyringe tips
Pipette 200 μL - 1 mL with appropriate plastic tips
2 mL amber Snap Top glass HPLC vials
1 mm Snap Caps for HPLC vials
HPLC kit with diode array detector Methanol (MeOH) HPLC Grade
Acetonitrile (ACN) Far UV HPLC Grade
Ultrapure de-ionised water
25 cm H5 ODS 5μ 4.6 mm i.d. HPLC column
Vortex mixer Ultrasonic bath
20 - 200 μL pipette with appropriate plastic tips
Aluminium weigh pans 5 mL glass volumetric flasks 2. Experimental procedure
2.1 1ml formulation vehicles were made up in triplicate by adding the appropriate volumes of alcohols and benzyl benzoate, and then adding castor oil by weight 2.2 Fulvestrant was then added to excess, until no more drug was seen to visibly dissolve. The weight of fulvestrant added was noted.
2.3 A magnetic stirrer bar was placed in each vial.
2.4 All the samples were overlaid with nitrogen and the vials were capped placed in the reaction block and stirred at a speed of 1000 at a temperature of 4°C 2.5 Using the PDP 20 - 200 μL pipettor, 200 μL aliquots were removed from each vial after 6 days and transferred to ultracentrifuge tubes. These tubes were centrifuged at a speed of 80,000 r.p.m. for 30 minutes at 25°C. 2.6 HPLC eluent was prepared by adding 1400 mL methanol, 450 mL water and 150 mL acetonitrile to a 2 litre plastic-coated solvent bottle. 2.7 990 μL HPLC eluent was added to 60 amber glass HPLC vials using a lmL Pipette.
2.8 3 x 10 μL of supernatant were removed from each ultracentrifuge tube using the Pipette PDP 0.5-25 μL pipette and added to the vials containing eluent.
2.9 The samples were diluted again 1 in 10. lOOμl sample was added to 900μl HPLC eluent
2.10 The amber vials were capped, vortex mixed for 10 seconds, sonicated for 10 minutes and then placed in the HPLC autosampler tray.
3. Calibration preparation
3.1 Approximately 10 mg fulvestrant was accurately weighed into an aluminium weigh pan on the microbalance and placed in a 5 mL glass volumetric flask The actual weight was recorded. 3.2 Approximately 4.5 mL HPLC eluent was added to the flask using a plastic pasteur pipette. The flask was then sonicated for 5 minutes prior to making accurately to volume (to give a spiking solution of approximately 2 mg.mL 1). 3.3 0 - 250 μL spiking solution was added to 2 mL amber HPLC vials using the appropriate Pipette and the volume made to 1 mL with HPLC eluent using a 1 mL Pipette as shown in the table below:
Figure imgf000025_0001
3.4 The HPLC vials were capped, vortexed for 10 seconds and placed on the HPLC autosampler tray. 3.5 A calibration was prepared (as per 3.1 - 3.4) for both batches of ICI 182780.
4. HPLC Conditions
Eluent : 70% MeOH / 22.5% Water / 7.5% ACN
Column : 25 cm 5μ Hypersil ODS 4.6 mm i.d. with guard column Detection wavelength : 280 nm
Flow rate : 1.2 mL.min"1
Temperature : Ambient
Injection volume : 50 μL
Retention time : 12 minutes approximately
Example 1
Pharmaceutical Formulations
Fulvestrant is mixed with ethanol and benzyl alcohol, stirring until completely dissolved. Benzyl benzoate is added and the solution is made to final weight with castor oil and stirred, (for convenience weight is used rather than volume by using the weight to volume ratio). The bulk solution is overlaid with nitrogen. The solution is sterilised by filtration using one or two filters of 0.2μm porosity. The sterile filtrate is kept under a nitrogen overlay as it is filled under aseptic conditions into washed and depyrogenised, sterile primary containers, for example vials or pre-filled syringes. An overage is included in the primary pack to 5 facilitate removal of the dose volume. The primary packs are overlaid with sterile nitrogen, before aseptically sealing. The process flow diagram below depicts the manufacturing process.
Quantities of each component of the formulation is chosen according to the required formulation specification, examples are described above. For example quantities are added of 10 each component to prepare the following formulations: a)
10% weight per volume of ethanol 20% weight per volume of benzyl alcohol 15% weight per volume of benzyl benzoate 15 500mg of fulvestrant for each 5ml of finished formulation and the remaining amount as castor oil b)
10% weight per volume of ethanol 20% weight per volume of benzyl alcohol 20 30% weight per volume of benzyl benzoate
500mg of fulvestrant for each 5ml of finished formulation and the remaining amount as castor oil c)
10% weight per volume of ethanol 25 20% weight per volume of benzyl alcohol 50% weight per volume of benzyl benzoate 500mg of fulvestrant for each 5ml of finished formulation and the remaining amount as castor oil d) 30 20% weight per volume of ethanol
20% weight per volume of benzyl alcohol 30% weight per volume of benzyl benzoate 500mg of fulvestrant for each 5ml of finished formulation and the remaining amount as castor oil e)
15% weight per volume of ethanol 5 10%) weight per volume of benzyl alcohol 50%) weight per volume of benzyl benzoate 500mg of fulvestrant for each 5ml of finished formulation and the remaining amount as castor oil f> 10 15%) weight per volume of ethanol
20% weight per volume of benzyl alcohol
30%) weight per volume of benzyl benzoate
500mg of fulvestrant for each 5ml of finished formulation and the remaining amount as castor oil 15
FLOW DIAGRAM OF MANUFACTURING
Ingredients/Components Process
Fulvestrant STAGE 1: DISSOLUTION OF Alcohol ACTIVE AGENT Benzyl Alcohol
*
Benzyl Benzoate STAGE 2: MIX
Figure imgf000028_0001
Castor Oil
STAG IE 4: STERILE FILTRATION
(0.2μm)
INTO BULK RECEIVING VESSEL
STAG IE 5: STERILE (0.2μm) IN-LINE FILTRATION
STAG 3 , AND iEE 66: ASEPTIC FILLING STOPPERING
STAG 3 tEE 77:: VISUAL INSPECTION
Example 2
Stability studies to 4 months for selection of stable 1 OOmg/ml Pharmaceutical formulations
Figure imgf000029_0001
Figure imgf000030_0001
The Control Sample refers to the following Pharmaceutical formulation: fulvestrant 50mg/ml, ethanol 10% w/v, benzylalcohol 10% w/v, benzyl benzoate 15% w/v and made to volume with castor oil.
Example 3
Pharmaceutical formulations selected for in vivo deposition and in vitro precipitation studies
Figure imgf000030_0002
A matrix of 7 pharmaceutical formulations (samples 3, 4, 5, 9, 12, 14 and 16 - see Example 3 below) was identified for further evaluation from in vitro precipitation and deposition studies. Sample 16 was a control. The precipitation experiment involved visual inspection of each sample under conditions where evaporation of alcohols led to precipitation of drug.
Example 4 In vivo Studies
Pharmaceutical formulations identified for further in vivo evaluation
Excipients (% /v) No. Fulvestrant (%w/v) Ethanol Benzyl Benzyl Castor
96% alcohol benzoate oil FI 10 10 20 15 45
F2 10 10 20 30 30
F3 10 10 20 50 10
F4 10 20 20 30 20
F5 10 15 10 50 15 F6 10 15 20 50 5
F7 10 15 20 30 25
Control 5 10 10 15 60
(a) An in vivo pharmacokinetic (PK) study on these 7 pharmaceutical formulations was performed over 3 months duration; results are shown in Figures 1, 2 and 3.
Analysis of PK results
Plasma levels were more variable than Control over the first 30 days; variability was similar to control thereafter. After 2 months, drug levels were equivalent to Control at 1 month indicating a prolonged period of action over Control. This release profile was surprising because, compared with Control which does not precipitate drug locally, local precipitation at the site of injection of the tested formulations was expected to impair their release profile.
Some differences in profiles were noted over the first 30 days such that they were divided into 2 groups (with Formulation F7 showing intermediate behaviour).
Group A, rapid release early time points (50%> Benzyl benzoate and low castor oil < 15%>) - see figure 2A
Group B, lower release, flatter profile (< 30% Benzyl benzoate and higher castor oil > 20%) - see figure 2B (b) Histopathology
Local tolerance was assessed to IM injection of the 7 pharmaceutical formulations and Control. Lesions were observed over a 51 day period. All pharmaceutical formulations caused tissue reactions greater than Control.
(c) Plasma levels for lOOmg dose at critical time points (ng/ml)
Form. Dose Time point (days)
(vas) 28 56 84
1 100 8.7 4.6 3.5
2 100 8.0 3.6 2.6
3 100 9.4 3.5 2.0
4 100 7.7 5.0 3.4 5 100 9.1 4.5 2.6
6 100 9.9 3.3 1.9
7 100 9.9 5.5 3.2
Control 50 3.3 1.7
Summary
Duration for lOOmg dose = min 2 months.
Duration for 150mg dose = min 3 months, (d) Measurement of Fulvestrant solubility in 7 pharmaceutical formulations after 6 days Formulation Solubility (mg/ml) 6days
FI 111 F2 140 F3 175 F4 235 F5 162 F6 212 F7 126 Example 5
Model for Fulvestrant Solubility
Formulation vehicles for Fulvestrant - solubility Measured
Fulvestrant Predicted Formulation 96% Benzyl Alcohol Benzyl Benzoate Castor oil Solubility solubility ETOH
No. % w/v % w/v % w/v % /v (mg/ml) (mg/ml)
Sample 1 5 5 0 to 100% 27 9.4
Sample 2 5 5 15 to 100% 36 32.8
Sample 3 10 5 0 to 100% 46 48.5
Sample 4 10 5 15 to 100% 54 36.6
Sample 5 10 10 0 to 100% 45 60.1
Sample 6 10 10 15 to 100% 65 72
Sample 7 15 15 0 to 100% 76 87.6
Sample 8 15 15 15 to 100% 102 111.1
Sample 9 11 22 17 to 100% 111 109.8
Sample 10 11 22 33 to 100% 140 166.1
Sample 11 11 22 56 to 100% 175 135.8
Sample 12 22 22 33 to 100% 235 174.4
Sample 13 17 11 56 to 100% 162 170.6
Sample 14 17 22 56 to 100% 212 200.9
Sample 15 17 22 33 to 100% 126 196.3
A linear regression model was fitted to solubility data from 15 samples using as independent variables the % ethanol, benzyl alcohol and benzyl benzoate levels in the formulations. The following model was obtained which had an R-Squared value of 93.2%: SOLUBILITY = -29.77 + 5.44 x ETOH + 2.38 x BA + 1.57 x BB Benzyl alcohol = BA, benzyl benzoate = BB, Ethanol = ETOH. Solubility measured as mg/ml See Figures 5 and 6 based on the following data measureedd lower predicted upper
C.L. C.L.
27 0 9.4 31.1
36 10 32.8 55.7
45 31.6 48.5 65.4
46 17.1 36.6 56.1
54 40.9 60.1 79.2
65 59 72 85
76 64.7 87.6 110.6
102 95.6 111.1 126.7
111 85.4 109.8 134.1
126 149 166.1 183.1 140 114.2 135.8 157.5
162 142.5 174.4 206.3
175 143.4 170.6 197.9
212 179.6 200.9 222.2
235 168.7 196.3 224
The table below shows predicted solubilities for a matrix of pharmaceutical formulations tested for stability. A good correlation was obtained with visual observations.
Formulation of Fulvestrant - stability
Predicted
Formulation Fulvestrant 95% Benzyl Alcohol Benzyl Benzoate Castor oil Observations solubility
ETOH
No. (mg/ml) % w/v % /v % w/v % w/v 4 months (mg/ml)
Sample 1 100 5 10 15 60 Precipitated 53.1
Sample 2 100 5 10 30 45 Precipitated 79.2
Sample 3 100 7.5 10 15 57.5 Precipitated 68.2
Sample 4 100 7.5 10 30 42.5 Precipitated 94.3
Sample 5 100 10 10 15 55 Precipitated 83.3
Sample 6 100 10 10 17.5 52.5 Precipitated 87.6
Sample 7 100 10 10 20 50 Precipitated 92.0
Sample 8 100 10 10 22.5 47.5 Solution 96.4
Sample 9 100 10 10 25 45 Solution 100.7
Sample 10 100 10 10 27.5 42.5 Solution 105.1
Sample 11 100 10 10 30 40 Solution 109.5
Sample 12 100 10 10 40 30 Solution 126.9
Sample 13 100 10 10 50 20 Solution 144.3
Sample 14 100 10 15 15 50 Solution 96.5
Sample 15 100 10 15 30 35 Solution 122.7
Sample 16 100 10 15 40 25 Solution 140.1
Sample 17 100 10 15 50 15 Solution 157.6
Sample 18 100 10 20 15 45 Solution 109.7
Sample 19 100 10 20 30 30 Solution 135.9
Sample 20 100 10 20 40 20 Solution 153.3
Sample 21 100 10 20 50 10 Solution 170.8
Sample 22 100 15 10 15 50 Solution 113.5
Sample 23 100 15 10 30 35 Solution 139.7
Sample 24 100 15 10 40 25 Solution 157.1
Sample 25 100 15 10 50 15 Solution 174.6
Sample 26 100 20 5 15 50 Solution 130.5
Sample 27 100 20 5 30 35 Solution 156.7
Sample 28 100 20 10 15 45 Solution 143.7
Sample 29 100 20 10 30 30 Solution 169.9
Sample 30 100 20 10 40 20 Solution 187.3
Sample 31 100 20 10 50 10 Solution 204.8
Sample 32 100 15 15 15 45 Solution 126.7
Sample 33 100 15 15 30 30 Solution 152.9
Sample 34 100 15 15 40 20 Solution 170.3
Sample 35 100 15 15 50 10 Solution 187.8
Sample 36 100 15 20 15 40 Solution 140.0
Sample 37 100 15 20 30 25 Solution 166.1
Sample 38 100 15 20 50 5 Solution 201.0 Sample 39 100 20 20 15 35 Solution 170.2
Sample 40 100 20 20 30 20 Solution 196.3
Control Sample 52.16 10 10 15 60 Solution 72.0
[Faslodex]
The Tables below show predicted formulations for various solubilities of fulvestrant; where an "X" means in solution. Note that the Tables include some impractical formulations where the sum of components becomes greater than 100%. The principal purpose is to illustrate the wide combinations of ethanol/ benzyl alcohol / benzyl benzoate taught by the invention to achieve different solubilities of fulvestrant.
Figure imgf000036_0001
Figure imgf000037_0001
Figure imgf000038_0001
Figure imgf000038_0002
Figure imgf000039_0001
Example 6
In-vivo Pharmacokinetic study using compositions at 140mg/ml of fulvestrant
Formulations F3 and F6 as described in Example 4 were modified to contain an increased level of fulvestrant to 140mg/ml. The modified formulations were named F8 and F9 as described below. Formulation Composition
The compositions of the formulations dosed in the PK study are shown in the table below.
Figure imgf000040_0001
PK Profile
The results are set out in Figure 7. The composition of the Control is the same as described in Example 4. Compositions F8 and F9 gave similar profiles with improved performance in terms of extended release of higher levels fulvestrant compared with Control.
Example 7
Compositions at 150mg/ml fulvestrant
Compositions analogous or similar to F3, F4, F5 and F6 (see Example 4) but comprising 150mg/ml of fulvestrant are prepared as follows.
Figure imgf000040_0002
Figure imgf000041_0001

Claims

Claims
1. A pharmaceutical formulation adapted for intramuscular injection comprising 100 mg/ml or more of fulvestrant, 10 % or more weight of a pharmaceutically acceptable alcohol per volume of formulation vehicle, 5 % or more weight of a pharmaceutically acceptable non- aqueous ester solvent per volume of formulation vehicle and 5 % or more weight of ricinoleate excipient per volume of formulation vehicle provided the formulation vehicle comprises at least 5 % weight of ethanol per volume of formulation vehicle and provided that the following formulation is excluded: fulvestrant up to 102 mg/ml, 15 % weight of ethanol per volume of formulation vehicle, 15 % weight of benzyl alcohol per volume of formulation vehicle, 15 % weight of benzyl benzoate per volume of formulation vehicle and 30 % or more weight of ricinoleate excipient per volume of formulation vehicle.
2. A pharmaceutical formulation adapted for intramuscular injection according to claim 2 comprising 105 mg/ml or more of fulvestrant, 10 % or more weight of a pharmaceutically acceptable alcohol per volume of formulation vehicle, 5 % or more weight of a pharmaceutically acceptable non-aqueous ester solvent per volume of formulation vehicle and 5 % or more weight of ricinoleate excipient per volume of formulation vehicle provided the formulation comprises at least 5 % weight of ethanol per volume of formulation vehicle.
3. A pharmaceutical formulation adapted for intramuscular injection according to claim 1 comprising 110 mg/ml or more of fulvestrant, 10 % or more weight of a pharmaceutically acceptable alcohol per volume of formulation vehicle, 5 % or more weight of a pharmaceutically acceptable non-aqueous ester solvent per volume of formulation vehicle and 5 % or more weight of ricinoleate excipient per volume of formulation vehicle provided the formulation vehicle comprises at least 5 % weight of ethanol per volume of formulation vehicle.
4. A pharmaceutical formulation adapted for intramuscular injection according to claim 1 comprising 115 mg/ml or more of fulvestrant, 10 % or more weight of a pharmaceutically acceptable alcohol per volume of formulation vehicle, 5 % or more weight of a pharmaceutically acceptable non-aqueous ester solvent per volume of formulation vehicle and 5 % or more weight of ricinoleate excipient per volume of formulation vehicle provided the formulation vehicle comprises at least 5 % weight of ethanol per volume of formulation vehicle.
5. A pharmaceutical formulation adapted for intramuscular injection according to claim 1 comprising 120 mg/ml or more of fulvestrant, 10 % or more weight of a pharmaceutically acceptable alcohol per volume of formulation vehicle, 5 % or more weight of a pharmaceutically acceptable non-aqueous ester solvent per volume of formulation vehicle and 5 % or more weight of ricinoleate excipient per volume of formulation vehicle provided the formulation vehicle comprises at least 5 % weight of ethanol per volume of formulation vehicle.
6. A pharmaceutical formulation adapted for intramuscular injection according to claim 1 comprising 130 mg/ml or more of fulvestrant, 15 % or more weight of a pharmaceutically acceptable alcohol per volume of formulation vehicle, 5 % or more weight of a pharmaceutically acceptable non-aqueous ester solvent per volume of formulation vehicle and 5 % or more weight of ricinoleate excipient per volume of formulation vehicle provided the formulation vehicle comprises at least 5 % weight of ethanol per volume of formulation vehicle.
7. A pharmaceutical formulation adapted for intramuscular injection according to claim 1 comprising 140 mg/ml or more of fulvestrant, 15 % or more weight of a pharmaceutically acceptable alcohol per volume of formulation vehicle, 12.5 % or more weight of a pharmaceutically acceptable non-aqueous ester solvent per volume of formulation vehicle and 5 % or more weight of ricinoleate excipient per volume of formulation vehicle provided the formulation vehicle comprises at least 10 % weight of ethanol per volume of formulation vehicle.
8. A pharmaceutical formulation adapted for intramuscular injection according to claim 1 comprising 150 mg/ml or more of fulvestrant, 15 % or more weight of a pharmaceutically acceptable alcohol per volume of formulation vehicle, 17.5 % or more weight of a pharmaceutically acceptable non-aqueous ester solvent per volume of formulation vehicle and 5 % or more weight of ricinoleate excipient per volume of formulation vehicle provided the formulation vehicle comprises at least 10 % weight of ethanol per volume of formulation vehicle.
9. A pharmaceutical formulation having a solubility for fulvestrant of at least Y mg/ml adapted for intramuscular injection comprising;
100 mg/ml or more of fulvestrant;
5% (w/v) or more castor oil per volume of formulation vehicle; and at least the following amounts (% weight/volume of formulation vehicle) of ethanol
(ETOH), benzyl alcohol (BA), benzyl benzoate (BB) determined by the algorithm:
Y = -29.77 + 5.44ETOH + 2.38BA + 1.57BB wherein Y is at least 100, ETOH is at least 5, BA is at least 5 and BB is at least 5.
10. A pharmaceutical formulation according to claim 9 wherein Y is selected from the group consisting of 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 170, 180, 190, and 200.
11. A pharmaceutical formulation according to claim 9 wherein Y is selected from the group consisting of 120, 125, 130, 135, 140, 145, 150, 155, 160, 170, 180, 190, and 200.
12. A pharmaceutical formulation according to claim 9 wherein Y is selected from the group consisting of 150, 155, 160, 170, 180, 190 and 200.
13. A pharmaceutical formulation according to claim 9 wherein Y is selected from 150, 155, 160, 170, 180, 190 and 200 and the formulation comprises at least 150mg/ml of fulvestrant.
14. A pharmaceutical formulation according to claim 9 wherein Y is 200 and the formulation comprises at least 200mg/ml of fulvestrant.
15. A pharmaceutical formulation comprising fulvestrant at a concentration of at least 100 mg/ml in which the formulation is adapted for intra-muscular injection into a human and which is capable after injection of attaining a therapeutically significant blood plasma fulvestrant concentration in a human for at least 2 months and provided that the following formulation is excluded: fulvestrant up to 102 mg/ml, 15 % weight of ethanol per volume of formulation vehicle, 15 % weight of benzyl alcohol per volume of formulation vehicle, 15 % weight of benzyl benzoate per volume of formulation vehicle and 30 % or more weight of ricinoleate excipient per volume of formulation vehicle.
16. A pharmaceutical formulation comprising fulvestrant at a concentration of at least 150 mg/ml in which the formulation is adapted for intra-muscular injection into a human and which is capable after injection of attaining a therapeutically significant blood plasma fulvestrant concentration in a human for at least 2 months.
17. Any one of the following pharmaceutical formulations comprising about: i)
10% weight per volume of ethanol
20% weight per volume of benzyl alcohol
15% weight per volume of benzyl benzoate
500-555mg of fulvestrant for each 5ml of finished formulation and the remaining amount as castor oil; ϋ)
10% weight per volume of ethanol
20% weight per volume of benzyl alcohol
30% weight per volume of benzyl benzoate
500-700mg of fulvestrant for each 5ml of finished formulation and the remaining amount as castor oil; iii)
10% weight per volume of ethanol
20% weight per volume of benzyl alcohol
50% weight per volume of benzyl benzoate
500-750mg of fulvestrant for each 5ml of finished formulation and the remaining amount as castor oil; iv)
20% weight per volume of ethanol
20% weight per volume of benzyl alcohol
30% weight per volume of benzyl benzoate 500-1175mg of fulvestrant for each 5ml of finished formulation and the remaining amount as castor oil; v)
15% weight per volume of ethanol
10% weight per volume of benzyl alcohol
50% weight per volume of benzyl benzoate
500-810 mg of fulvestrant for each 5ml of finished formulation and the remaining amount as castor oil; vi)
15% weight per volume of ethanol
20% weight per volume of benzyl alcohol
50% weight per volume of benzyl benzoate
500 mg of fulvestrant for each 5ml of finished formulation and the remaining amount as castor oil; vii)
15% weight per volume of ethanol
20% weight per volume of benzyl alcohol
30% weight per volume of benzyl benzoate
500-630mg of fulvestrant for each 5ml of finished formulation and the remaining amount as castor oil; viii)
10% weight per volume of ethanol
20% weight per volume of benzyl alcohol
50% weight per volume of benzyl benzoate
750mg of fulvestrant for each 5ml of finished formulation and the remaining amount as castor oil; ix)
20% weight per volume of ethanol
20% weight per volume of benzyl alcohol
30% weight per volume of benzyl benzoate
750mg of fulvestrant for each 5ml of finished formulation and the remaining amount as castor oil; x)
15% weight per volume of ethanol
10% weight per volume of benzyl alcohol
50% weight per volume of benzyl benzoate
750mg of fulvestrant for each 5ml of finished formulation and the remaining amount as castor oil; xi)
9% weight per volume of ethanol
19% weight per volume of benzyl alcohol
47% weight per volume of benzyl benzoate
700mg of fulvestrant for each 5ml of finished formulation and the remaining amount as castor oil; xii)
14% weight per volume of ethanol
19% weight per volume of benzyl alcohol
48% weight per volume of benzyl benzoate
700mg of fulvestrant for each 5ml of finished formulation and the remaining amount as castor oil; xiii)
15% weight per volume of ethanol
20% weight per volume of benzyl alcohol
45% weight per volume of benzyl benzoate
750mg of fulvestrant for each 5ml of finished formulation and the remaining amount as castor oil; xiv)
9% weight per volume of ethanol
19% weight per volume of benzyl alcohol
47% weight per volume of benzyl benzoate
750mg of fulvestrant for each 5ml of finished formulation and the remaining amount as castor oil; xv)
19% weight per volume of ethanol
19% weight per volume of benzyl alcohol 28% weight per volume of benzyl benzoate 750mg of fulvestrant for each 5ml of finished formulation and the remaining amount as castor oil; xvi)
14% weight per volume of ethanol 9% weight per volume of benzyl alcohol 47% weight per volume of benzyl benzoate 750mg of fulvestrant for each 5ml of finished formulation and the remaining amount as castor oil; xvii)
14% weight per volume of ethanol 19% weight per volume of benzyl alcohol 47% weight per volume of benzyl benzoate 750mg of fulvestrant for each 5ml of finished formulation and the remaining amount as castor oil; xviii)
10% weight per volume of ethanol 20% weight per volume of benzyl alcohol 45% weight per volume of benzyl benzoate 750mg of fulvestrant for each 5ml of finished formulation and the remaining amount as castor oil; xix)
15% weight per volume of ethanol 10% weight per volume of benzyl alcohol 45% weight per volume of benzyl benzoate 750mg of fulvestrant for each 5ml of finished formulation and the remaining amount as castor oil; xx)
20% weight per volume of ethanol 20% weight per volume of benzyl alcohol 25% weight per volume of benzyl benzoate 750mg of fulvestrant for each 5ml of finished formulation and the remaining amount as castor oil; xxi)
10% weight per volume of ethanol
30% weight per volume of benzyl alcohol
25% weight per volume of benzyl benzoate
750mg of fulvestrant for each 5ml of finished formulation and the remaining amount as castor oil; xxii)
10% weight per volume of ethanol
25% weight per volume of benzyl alcohol
30% weight per volume of benzyl benzoate
750mg of fulvestrant for each 5ml of finished formulation and the remaining amount as castor oil; xxiii)
10% weight per volume of ethanol
30% weight per volume of benzyl alcohol
30% weight per volume of benzyl benzoate
750mg of fulvestrant for each 5ml of finished formulation and the remaining amount as castor oil; xxiv)
15% weight per volume of ethanol
25% weight per volume of benzyl alcohol
30% weight per volume of benzyl benzoate
750mg of fulvestrant for each 5ml of finished formulation and the remaining amount as castor oil; xxv)
15% weight per volume of ethanol
25% weight per volume of benzyl alcohol
25% weight per volume of benzyl benzoate
750mg of fulvestrant for each 5ml of finished formulation and the remaining amount as castor oil; and xxvi)
15% weight per volume of ethanol
20% weight per volume of benzyl alcohol 30% weight per volume of benzyl benzoate
750mg of fulvestrant for each 5ml of finished formulation and the remaining amount as castor oil.
18. A pharmaceutical formulation as claimed in any preceding claim wherein the pharmaceutically-acceptable alcohol is a mixture of ethanol and benzyl alcohol.
19. A pharmaceutical formulation as claimed in any preceding claim wherein the pharmaceutically-acceptable non-aqueous ester solvent is selected from benzyl benzoate, ethyl oleate, isopropyl myristate, isopropyl palmitate or a mixture of any thereof.
20. A pharmaceutical formulation as claimed in any preceding claim wherein the pharmaceutically-acceptable non-aqueous ester solvent is benzyl benzoate.
21. A pharmaceutical formulation as claimed in any preceding claim wherein the ricinoleate excipient is castor oil.
22. A unit dose of a pharmaceutical formulation as claimed in any preceding claim wherein the total volume of the formulation is 6ml or less.
23. A pharmaceutical formulation adapted for intramuscular injection, as defined in any preceding claim for use in medical therapy.
24. Use of fulvestrant in the preparation of a pharmaceutical formulation, as defined in any preceding claim for the treatment of a benign or malignant disease of the breast or reproductive tract.
25. Use of fulvestrant in the preparation of a pharmaceutical formulation, as defined in any preceding claim for the treatment of a benign or malignant disease of the breast or reproductive tract in a human with dosage intervals of at least 8 weeks.
26. A sterile syringe or vial comprising a pharmaceutical formulation as defined in any preceding claim.
PCT/GB2002/003092 2001-07-07 2002-07-03 Pharmaceutical formulation for the intramuscular administration of fulvestrant WO2003006064A1 (en)

Priority Applications (9)

Application Number Priority Date Filing Date Title
JP2003511869A JP2004534093A (en) 2001-07-07 2002-07-03 Pharmaceutical formulation for intramuscular administration of fulvestrant
CA002453111A CA2453111A1 (en) 2001-07-07 2002-07-03 Pharmaceutical formulation for the intramuscular administration of fulvestrant
HU0400115A HUP0400115A3 (en) 2001-07-07 2002-07-03 Pharmaceutical composition for the intramuscular administration of fulvestrant
EP02740940A EP1406662A1 (en) 2001-07-07 2002-07-03 Pharmaceutical formulation for the intramuscular administration of fulvestrant
KR10-2004-7000153A KR20040010841A (en) 2001-07-07 2002-07-03 Pharmaceutical formulation for the intramuscular administration of fulvestrant
IL15957602A IL159576A0 (en) 2001-07-07 2002-07-03 Pharmaceutical formulation for the intramuscular administration of fulvestrant
BR0210898-4A BR0210898A (en) 2001-07-07 2002-07-03 Pharmaceutical formulation, unit dose thereof, use of powder in the preparation of a pharmaceutical formulation, and sterile syringe or vial
IS7097A IS7097A (en) 2001-07-07 2004-01-05 Medicinal product for the administration of intramuscular filvestrant
NO20040047A NO20040047L (en) 2001-07-07 2004-01-06 Pharmaceutical formulation for intramuscular administration of fulvestrant

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
GBGB0116619.8A GB0116619D0 (en) 2001-07-07 2001-07-07 Formulation
GB0116619.8 2001-07-07
US31571101P 2001-08-30 2001-08-30
US60/315,711 2001-08-30

Publications (1)

Publication Number Publication Date
WO2003006064A1 true WO2003006064A1 (en) 2003-01-23

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Country Status (15)

Country Link
EP (1) EP1406662A1 (en)
JP (1) JP2004534093A (en)
CN (1) CN1553815A (en)
AR (1) AR037138A1 (en)
BR (1) BR0210898A (en)
CA (1) CA2453111A1 (en)
CO (1) CO5560585A2 (en)
HU (1) HUP0400115A3 (en)
IL (1) IL159576A0 (en)
IS (1) IS7097A (en)
MX (1) MXPA04000028A (en)
NO (1) NO20040047L (en)
PL (1) PL367624A1 (en)
RU (1) RU2004102393A (en)
WO (1) WO2003006064A1 (en)

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US8329680B2 (en) 2000-01-10 2012-12-11 Astrazeneca Ab Formulation
US9271990B2 (en) 2014-02-14 2016-03-01 Fresenius Kabi Usa, Llc Fulvestrant formulations
WO2017193048A1 (en) * 2016-05-06 2017-11-09 Eagle Pharmaceuticals, Inc. Fulvestrant formulations and methods of their use
WO2019094650A1 (en) * 2017-11-08 2019-05-16 Eagle Pharmaceuticals, Inc Fulvestrant formulations and methods of their use
WO2019113361A1 (en) * 2017-12-07 2019-06-13 Nevakar Inc. Concentrated fulvestrant compositions
US10568890B2 (en) 2012-03-31 2020-02-25 Xi'an Libang Pharmaceutical Co., Ltd Lactate-based fulvestrant or fulvestrant derivative oily preparation and preparation method thereof
CN111465398A (en) * 2018-01-31 2020-07-28 富士胶片株式会社 Method for producing injection preparation
US10772895B2 (en) 2016-04-06 2020-09-15 Fujifilm Corporation Pharmaceutical composition
WO2021115389A1 (en) * 2019-12-11 2021-06-17 上海博志研新药物技术有限公司 Fulvestrant pharmaceutical composition, preparation method therefor, and application thereof
RU2775225C2 (en) * 2016-05-06 2022-06-28 Игл Фармасьютикалз, Инк. Fulvestrant compositions and their application methods
US11590077B2 (en) 2016-05-06 2023-02-28 Eagle Pharmaceuticals, Inc. Fulvestrant formulations and methods of their use
CN118717660A (en) * 2024-06-12 2024-10-01 湖州亚瑟制药有限公司 Fulvestrant pharmaceutical composition for injection and preparation method thereof

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JP5809624B2 (en) 2009-08-31 2015-11-11 シーアン リーバン ファーマシューティカル テクノロジー シーオー．， エルティーディー．Ｘｉ’Ａｎ Ｌｉｂａｎｇ Ｐｈａｒｍａｃｅｕｔｉｃａｌ Ｔｅｃｈｎｏｌｏｇｙ Ｃｏ．， Ｌｔｄ． Fulvestrant nanospheres / microspheres and their preparation and use
CN102600064A (en) * 2012-03-31 2012-07-25 西安力邦制药有限公司 Fulvestrant or fulvestrant derivative sustained release preparation and preparation method thereof
CN102600065B (en) * 2012-03-31 2014-08-13 莱普德制药有限公司 Fulvestrant or fulvestrant derivative oily preparation and preparation method thereof
WO2017208847A1 (en) 2016-05-31 2017-12-07 富士フイルム株式会社 Pharmaceutical composition
CN111481559B (en) * 2019-01-25 2021-10-08 江苏恒瑞医药股份有限公司 High-concentration fulvestrant composition and preparation method thereof

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US8466139B2 (en) 2000-01-10 2013-06-18 Astrazeneca Ab Formulation
US8329680B2 (en) 2000-01-10 2012-12-11 Astrazeneca Ab Formulation
US10568890B2 (en) 2012-03-31 2020-02-25 Xi'an Libang Pharmaceutical Co., Ltd Lactate-based fulvestrant or fulvestrant derivative oily preparation and preparation method thereof
US9271990B2 (en) 2014-02-14 2016-03-01 Fresenius Kabi Usa, Llc Fulvestrant formulations
US11229655B2 (en) 2014-02-14 2022-01-25 Fresenius Kabi Usa, Llc Fulvestrant formulations
US9833459B2 (en) 2014-02-14 2017-12-05 Fresenius Kabi Usa, Llc Fulvestrant formulations
US10188663B2 (en) 2014-02-14 2019-01-29 Fresenius Kabi Usa, Llc Fulvestrant formulations
US10772895B2 (en) 2016-04-06 2020-09-15 Fujifilm Corporation Pharmaceutical composition
WO2017193048A1 (en) * 2016-05-06 2017-11-09 Eagle Pharmaceuticals, Inc. Fulvestrant formulations and methods of their use
AU2017261321B2 (en) * 2016-05-06 2023-03-09 Eagle Pharmaceuticals, Inc. Fulvestrant formulations and methods of their use
US11590077B2 (en) 2016-05-06 2023-02-28 Eagle Pharmaceuticals, Inc. Fulvestrant formulations and methods of their use
RU2775225C2 (en) * 2016-05-06 2022-06-28 Игл Фармасьютикалз, Инк. Fulvestrant compositions and their application methods
IL274433B1 (en) * 2017-11-08 2024-03-01 Eagle Pharmaceuticals Inc Fulvestrant formulations and methods of their use
WO2019094650A1 (en) * 2017-11-08 2019-05-16 Eagle Pharmaceuticals, Inc Fulvestrant formulations and methods of their use
RU2800869C2 (en) * 2017-11-08 2023-07-31 Игл Фармасьютикалз, Инк Fulvestrant compositions and methods of their use
IL274433B2 (en) * 2017-11-08 2024-07-01 Eagle Pharmaceuticals Inc Fulvestrant formulations and methods of using them
US12186427B2 (en) 2017-11-08 2025-01-07 Eagle Pharmaceuticals, Inc. Fulvestrant formulations and methods of their use
WO2019113361A1 (en) * 2017-12-07 2019-06-13 Nevakar Inc. Concentrated fulvestrant compositions
CN111465398A (en) * 2018-01-31 2020-07-28 富士胶片株式会社 Method for producing injection preparation
WO2021115389A1 (en) * 2019-12-11 2021-06-17 上海博志研新药物技术有限公司 Fulvestrant pharmaceutical composition, preparation method therefor, and application thereof
CN118717660A (en) * 2024-06-12 2024-10-01 湖州亚瑟制药有限公司 Fulvestrant pharmaceutical composition for injection and preparation method thereof

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IS7097A (en) 2004-01-05
CN1553815A (en) 2004-12-08
IL159576A0 (en) 2004-06-01
BR0210898A (en) 2004-06-22
MXPA04000028A (en) 2004-05-21
CA2453111A1 (en) 2003-01-23
EP1406662A1 (en) 2004-04-14
RU2004102393A (en) 2005-03-27
PL367624A1 (en) 2005-03-07
NO20040047L (en) 2004-02-23
JP2004534093A (en) 2004-11-11
AR037138A1 (en) 2004-10-27
CO5560585A2 (en) 2005-09-30
HUP0400115A3 (en) 2005-11-28
HUP0400115A2 (en) 2004-06-28

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